WO2011149827A1 - Compounds and methods - Google Patents

Compounds and methods Download PDF

Info

Publication number
WO2011149827A1
WO2011149827A1 PCT/US2011/037533 US2011037533W WO2011149827A1 WO 2011149827 A1 WO2011149827 A1 WO 2011149827A1 US 2011037533 W US2011037533 W US 2011037533W WO 2011149827 A1 WO2011149827 A1 WO 2011149827A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
benzenesulfonamide
amino
pyrimidin
alkyl
Prior art date
Application number
PCT/US2011/037533
Other languages
French (fr)
Inventor
Marlys Hammond
Lara S. Kallander
Brian Griffin Lawhorn
Joanne Philp
Martha A. Sarpong
Mark Andrew Seefeld
Original Assignee
Glaxosmithkline Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Publication of WO2011149827A1 publication Critical patent/WO2011149827A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that inhibit TNNI3K and B-Raf kinase and methods of making and using the same. Specifically, the present invention relates to anilino-deazapurines, anilino-purines, and anilino-pyrazolopyrimidines as TNNI3K and B-Raf kinase inhibitors.
  • Cardiac troponin l-interacting kinase (TNNI3K), also known as CARK (for cardiac ankyrin repeat kinase), is a protein kinase that exhibits highly selective expression for cardiac tissues and has been shown to interact with components of the sarcomere, including troponin I (Zhao, Y. et al., J. Mol. Med., 2003, 81, 297-304; Feng, Y. et al., Gen. Physiol. Biophys., 2007, 26, 104-109; Wang, H. et al., J. Cell. Mol. Med., 2008, 12, 304- 315).
  • TNNI3K a cardiac-specific kinase, promotes cardiac hypertrophy in vivo
  • Inhibition of the kinase activity of TNNI3K may disrupt these signaling pathways, and enable the mitigation and/or reversal of cardiac hypertrophy seen in patients with progressively worsening heart failure.
  • the heart In response to mechanical, neurohormonal, and genetic stimuli, the heart will undergo hypertrophy, or muscle growth and remodeling, in order to maintain sufficient cardiac output to meet tissue oxygen demands. While these structural changes are initially seen as compensatory, sustained dysregulation of hypertrophic signaling can lead to heart failure, the pathophysiological state in which the heart can no longer adequately function as a pump (Mudd, J. O. and Kass, D. A., Nature, 2008, 451, 919-928).
  • Heart failure is responsible for a reduced quality of life and premature death in a significant proportion of sufferers, and is characterized by impaired cardiac function either due to reduced pump function (systolic dysfunction) or reduced filling (diastolic
  • Congestive heart failure is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. The prevalence of heart failure is anticipated to increase with ageing populations, prompting a need for new and improved methods of treating heart failure.
  • Both receptor tyrosine kinases and serine/threonine kinases have been implicated in cellular signaling pathways that control cell function, division, growth, differentiation, and death (apoptosis) through reversible phosphorylation of the hydroxyl groups of tyrosine or serine and threonine residues, respectively, in proteins.
  • signal transduction for example, extracellular signals are transduced via membrane receptor activation, with amplification and propagation using a complex choreography of cascades of protein phosphorylation, and protein dephosphorylation events to avoid uncontrolled signaling.
  • Receptor tyrosine kinases catalyze phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which govern cell growth, proliferation and differentiation. Downstream of the several rtKs lie several signaling pathways, among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases.
  • kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2.
  • This signaling pathway also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals. The ultimate function of this is to link receptor activity at the cell membrane with modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival. Mutations in various Ras GTPases and the B-Raf kinase have been identified that can lead to sustained and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival.
  • MAPK mitogen-activated protein kinase
  • cervical cancer (Moreno-Bueno et al., Clin. Cancer Res. (2006) 12 3865-3866), cholangiocarcinoma (Tannapfel et al., Gut (2003) 52 706-712),
  • central nervous system tumors including primary CNS tumors such as
  • glioblastomas astrocytomas and ependymomas
  • secondary CNS tumors i.e., metastases to the central nervous system of tumors originating outside of the central nervous system
  • colorectal cancer including large intestinal colon carcinoma (Yuen et al., Cancer Res. (2002) 62 6451 -6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006), 63 1314-1330),
  • leukemias Garnett et al., Cancer Cell (2004) supra
  • acute lymphoblastic leukemia Garnett et al., Cancer Cell (2004) supra and Gustafsson et al., Leukemia (2005) 19 310-312
  • AML acute myelogenous leukemia
  • myelodysplastic syndromes Christiansen et al., Leukemia (2005) supra
  • chronic myelogenous leukemia Mizuchi et al., Biochem. Biophys. Res. Commun.
  • Hodgkin's lymphoma (Figl et al., Arch. Dermatol. (2007) 143 495-499), non- Hodgkin's lymphoma (Lee et al., Br. J. Cancer (2003) 89 1958-1960), megakaryoblastic leukemia (Eychene et al., Oncogene (1995) 10 1 159-1 165) and multiple myeloma (Ng et al., Br. J. Haematol. (2003) 123 637-645),
  • ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203 617-619 and Davies (2002) supra), endometrial cancer (Garnett et al., Cancer Cell (2004) supra, and Moreno- Bueno et al., Clin. Cancer Res. (2006) supra),
  • pancreatic cancer (Ishimura et al., Cancer Lett. (2003) 199 169-173)
  • c-Raf Overexpression of c-Raf has been linked to AML (Zebisch et al., Cancer Res. (2006) 66 3401-3408, and Zebisch ⁇ Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et la., Cell. Mol. Life Sci. (2006).
  • Raf family kinases By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A.J., et al., (2006) Cancer Res. 66 1 1 100-1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases will be useful for the treatment of such cancers or other condition associated with Raf kinase.
  • the invention is directed to novel anilino-deazapurines, anilino-purines, and anilino- pyrazolopyrimidines. Specifically, the invention is directed to a compound according to Formula I:
  • R 1 is (Ci-C 4 )alkyl
  • X is N or CH
  • Y is N or CR 4 ;
  • Z is N or CR 4 ;
  • R 2 is H, halogen, (d-C 8 )alkyl, (C C 8 )haloalkyl, hydroxy(C C 8 )alkyl-,
  • each R a is (C 1 -C 4 )alkyl, which is optionally substituted one to three times, independently, by halogen, hydroxyl, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino,
  • each R b is H or (d-d)alkyl
  • R a and R b taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, amino,
  • (C 1 -C 4 )alkylamino ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, oxo, (Ci-C 4 )alkoxy, (Ci-C 4 )haloalkoxy, (Ci-C 4 )alkoxy(CrC 4 )alkyl, or cyano;
  • R 3 is H
  • R 2 and R 3 taken together with atoms through which they are connected form a non-aromatic 5-membered ring, which may be unsubstituted or substituted with one or two substituents independently selected from (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl,
  • each R 4 is independently selected from H, halogen, cyano, (Ci-C 8 )alkyl,
  • aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (d-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (d-d)haloalkyl, cyano, nitro, -OR c , -N(R d )(R e ), -CON(R d )(R e ), -C0 2 R c , -CO(d-C 4 )alkyl, -S0 2 N(R d )(R e ),
  • R c is H, (Ci-C 6 )alkyl, (d-C 8 )cycloalkyl, or -(d-C 4 )alkyl(C 3 -C 8 )cycloalkyl, wherein said (d-C 6 )alkyl or (C 3 -C 8 )cycloalkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)haloalkyl, (d-d)alkoxy, amino,
  • (d-C 4 )alkylamino ((Ci-d)alkyl)((C d)alkyl)amino, -C0 2 H, -C0 2 (d-C 4 )alkyl, -CONH 2 , -CONH(Ci-d)alkyl, -CON((Ci-d)alkyl)((C d)alkyl), heterocycloalkyl, or aryl, wherein said aryl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)alkyl, (d-d)haloalkyl, (d-d)alkoxy, (d-d)haloalkoxy, hydroxy(d-d)alkyl-, amino, (C 1 -d)alkylamino, or ((C 1 -d)alkyl)((C 1 -d)alkyl)amino, -CONH 2 , -CONH(Ci
  • R d is independently selected from H, (Ci-C )alkyl, aryl, heterocycloalkyi or heterocycloalkyl-(Ci-C 2 )alkyl, wherein said (Ci-C )alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (CrC )alkoxy, amino, (Ci-C )alkylamino, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, -C0 2 H, -C0 2 (C C 4 )alkyl, -CONH 2 , -CONH(Ci-C 4 )alkyl, or -CON((Ci-C )alkyl)((CrC )alkyl), and wherein any heterocycloalkyi is optionally substituted by (Ci-C )alkyl;
  • R e is (Ci-C 4 )alkyl
  • R d and R e taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (Ci-C )alkyl, (Ci-C )haloalkyl, amino,
  • R is H, (Ci-C )alkyl, cycloalkyl, 5-6-membered heterocycloalkyi, phenyl, or 5-6- membered heteroaryl, wherein said (C 1 -C 4 )alkyl, cycloalkyl, 5-6-membered
  • heterocycloalkyi, phenyl, or 5-6-membered heteroaryl is optionally substituted one to three times, independently, by (C 1 -C 4 )alkyl, hydroxyl, (CrC 4 )alkoxy, amino, (C 1 -C 4 )alkylamino, ((C C ⁇ alkylXid-C ⁇ alky amino;
  • the compounds of the invention are inhibitors of TNNI3K and can be useful for the treatment of cardiac diseases and disorders, particularly heart failure.
  • the compounds of the invention are also inhibitors of B-Raf kinase and can be useful for the treatment of susceptible neoplasms.
  • This invention is directed to pharmaceutical compositions comprising a compound of the invention or a salt, particularly a pharmaceutical salt, thereof.
  • One embodiment of this invention is directed to methods of inhibiting TNNI3K and treatment of conditions associated therewith comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a salt thereof.
  • Another embodiment of this invention is directed to a method of treating a susceptible neoplasm in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a salt thereof.
  • Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system);
  • primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas
  • secondary CNS tumors i.e., metastases to the central nervous system of tumors originating outside of the central nervous system
  • colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
  • leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelody
  • alkyl represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, pentyl, and hexyl.
  • C1-C4" refers to an alkyl containing from 1 to 4 carbon atoms.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as “haloalkyl”, “hydroxyalkyl”, or “alkoxyalkyl”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon double bonds. Examples include ethenyl and propenyl.
  • alkynyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon triple bonds. Examples include ethynyl and propynyl.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring.
  • (C 3 -C 8 )cycloalkyl refers to a non-aromatic cyclic
  • hydrocarbon ring having from three to eight ring carbon atoms.
  • exemplary "(C 3 -C 8 )cycloalkyl” groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkoxy means an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom.
  • the term “(CrC 4 )alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary "(d-C 4 )alkoxy” groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.
  • Alkylthio- means an alkyl radical containing the specified number of carbon atoms attached through a sulfur linking atom.
  • the term “(CrC 4 )alkylthio-” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through a sulfur linking atom.
  • Exemplary "(CrC 4 )alkylthio-” groups useful in the present invention include, but are not limited to, methylthio-, ethylthio-, n-propylthio-, isopropylthio-, n-butylthio-, s-butylthio-, and f-butylthio-.
  • Cycloalkyloxy and “cycloalkylthio” means a saturated carbocyclic ring containing
  • cycloalkyloxy moieties include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Aryl represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be
  • aryl is phenyl
  • Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
  • Heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also
  • bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzo
  • heteroaryl groups present in the compounds of this invention are 5-membered and/or 6-memebred monocyclic heteroaryl groups.
  • Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms.
  • Selected 5- or 6-membered heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • Heterocycloalkyl represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, hexahydro-1 H- 1 ,4-diazepinyl, azabicylo[3.2.1 ]
  • heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3- dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, and hexahydro-1 /-/-1 ,4-diazepinyl.
  • heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thi
  • halogen and halo represent chloro, fluoro, bromo or iodo substituents.
  • Hydrox or hydroxyl is intended to mean the radical -OH.
  • compound(s) of the invention means a compound of Formula I (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • any salt or non-salt form e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof
  • any physical form thereof e.g., including non-solid forms (e.
  • the term ""optionally substituted” indicates that a group, such as alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent(s) as defined. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
  • R 1 is (C 1 -C 4 )alkyl.
  • R 1 is methyl or ethyl.
  • X is N or CH. In a specific embodiment of this invention, X is CH.
  • Y is N or CR 4 and Z is N or CR 4 .
  • Y and Z are each independently CR 4 .
  • Such compounds of the invention may be depicted according to Formula la:
  • Y is CR 4 and Z is N.
  • pounds of the invention may be depicted according to Formula lb:
  • Y is N and Z is CR 4 .
  • Such compounds of the invention may be depicted according to Formula Ic:
  • R 2 is H, halogen, (C C 8 )alkyl, (d-C 8 )haloalkyl, hydroxy(C C 8 )alkyl-, (Ci-Ce)alkylthio-, (C C 8 )haloalkylthio-, (C 3 -C 8 )cycloalkylthio-, aryl, heteroaryl, -N(R a )(R b ), or -OR c ; wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC 6 )alkyl, (Ci-C 4 )haloalkyl, hydroxyl, (Ci-C 6 )alkoxy,
  • R 2 is H, F, CI, Br, (CrC 6 )alkyl
  • (C 1 -C 4 )haloalkyl cyano, hydroxyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, hydroxy(C 1 -C 4 )alkyl-, (Ci-C 4 )alkoxy(CrC 4 )alkyl-, amino, (Ci-C 4 )alkylamino, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino.
  • R 2 is H, F, CI, methyl, phenyl, 1-methyl- pyrazol-5-yl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, n-propoxy, 3,3,3-trifluoro-n-propoxy, n-butoxy, s-butoxy, 1-methyl-3,3,3-trifluoro-n-propoxy,
  • R 3 is H.
  • R 2 and R 3 taken together with atoms through which they are connected form a non-aromatic 5-membered ring, which may be unsubstituted or substituted with one or two substituents independently selected from (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, hydroxy(Ci-C 4 )alkyl-, (Ci-C 4 )alkoxy, (Ci-C 4 )haloalkoxy, (Ci-C 4 )alkylthio-, (C C 4 )haloalkylthio-; -C0 2 R , -(C C 4 )alkyl-C0 2 R , -COR f , -CON(R d )(R e ), and -(C C 4 )alkyl-CON(R d )(R e ).
  • R 2 and R 3 taken together represent -CH 2 CH 2 -.
  • each R 4 is independently selected from H, halogen, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C C 4 )haloalkyl, (C C 4 )alkoxy,
  • aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC 6 )alkyl, (C 3 -C 6 )cycloalkyl, (CrC 4 )haloalkyl, cyano, nitro, -OR c , -N(R d )(R e ), -CON(R d )(R e ), -C0 2 R c , -CO(C C 4 )alkyl, -S0 2 N(R d )(R e ),
  • each R 4 is independently selected from H, F, CI, Br, (C C 6 )alkyl, (d-C 4 )haloalkyl, (C C 4 )alkoxy, (d-C 4 )haloalkoxy, (C C 4 )alkylthio-, cyano, -C0 2 H, -C0 2 (C C 4 )alkyl, -CONH 2 , -CONH(C C 4 )alkyl-,
  • -NHCO(Ci-C 4 )alkyl phenyl, halophenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl.
  • At least one R 4 is H, F, CI, Br, methyl, isopropyl, isobutyl, cyano, carboxy, isopropyloxycarbonyl, f-butyloxycarbonyl, pyrrolidin-1 - ylcarbonyl, furan-2-yl, furan-3-yl, 5-methyl-furan-2-yl, 1-methyl-pyrazol-4-yl, 1-methyl- pyrazol-5-yl, 3,6-dihydro-2H-pyran-4-yl, phenyl, 4-fluorophenyl, 2-chlorophenyl,
  • Representative compounds of this invention include the compounds of Examples
  • the compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • polymorphism i.e. the capacity to occur in different crystalline forms. These different crystalline forms are typically known as "polymorphs.” It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • solvates of the compounds of the invention, or salts thereof, that are in crystalline form may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • the compounds of this invention are bases, wherein a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesul
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
  • hydroxybenzoates methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ -hydroxybutyrates, glycollates, tartrates, mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates and naphthalene-2-sulfonates.
  • Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • a suitable base Such a
  • pharmaceutically acceptable salt may be made with a base which affords a
  • pharmaceutically acceptable cation which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, ⁇ /, ⁇ /'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
  • alkali metal salts especially sodium and potassium
  • alkaline earth metal salts especially calcium and magnesium
  • aluminum salts and ammonium salts as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, ⁇ /, ⁇ /'-di
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • a disclosed compound containing a carboxylic acid or other acidic functional group is isolated as a salt
  • the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK a than the free acid form of the compound.
  • the compounds of Formula I may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different R 1 , R 2 , and R 3 groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula I, they are illustrative of processes that may be used to make the compounds of the invention.
  • the compounds of Formula I can be prepared under a variety of conditions by reaction of an aryl/heteroaryl amine (e.g., Ar- NH-R 3 ) with an activated pyrrolopyrimidine.
  • an aryl/heteroaryl amine e.g., Ar- NH-R 3
  • Ar-NH-R 3 AgOTf, DMF, 80-100 °C, 5-20 h; b) Ar-NH-R 3 , isopropanol, ⁇ w, 100-150 °C, 10-25 min; c) Ar-NH-R 3 , AgOTf, isopropanol, ⁇ w, 100- 160 °C, 0.5-1 .25 h; d) Ar-NH-R 3 , AgOTf, isopropanol, ⁇ w, 80 °C, 16-42 h; e) Ar-NH-R 3 , isopropanol, aq. HCI, ⁇ , 150 °C, 30-60 min; f) ArNH-R 3 , 1 ,4- dioxane, AcOH, 90 °C, 24 h
  • the compounds of Formula I can be prepared under a variety of conditions by reaction of an aryl/heteroaryl amine (e.g., Ar-NH-R 3 ) with an activated pyrrolopyrimidine, pyrazolopyrimidine, or imidazopyrimidine.
  • an aryl/heteroaryl amine e.g., Ar-NH-R 3
  • Ar-NH-R 3 isopropanol, 80 °C, 16-42 h; b) Ar-NH-R 3 , DMF, AgOTf, 80 °C, 16-20 h; c) Ar-NH-R 3 , 1 ,4-dioxane, AgOTf, 80-100 °C, 16-72 h; d) Ar-NH-R 3 , 1 ,4-dioxane, DIPEA, 80-100 °C, 16-72 h; e) Ar-NH-R 3 , 1 ,4- dioxane, AcOH, 80-100 °C, 20-72 h
  • the invention also includes various deuterated forms of the compounds of Formula
  • deuterated alkyl groups (/V-(deuteromethyl) amines or R a /R b or R d /R e alkyls) may be prepared by conventional techniques (see for example: methyl-c/3-amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).
  • Scheme 1 or Scheme 2 Employing such compounds according to Scheme 1 or Scheme 2 will allow for the compounds of Formula I in which various hydrogen atoms of the /V-methyl, phenyl or pyrimidinyl groups are replaced with a deuterium atom.
  • the present invention is directed to a method of inhibiting TNNI3K which comprises contacting the kinase with a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
  • This invention is also directed to a method of treatment of a TNNI3K-mediated disease or disorder comprising administering an effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof.
  • patient refers to a human or other mammal.
  • this invention is directed to a method of inhibiting TNNI3K activity, comprising contacting the kinase with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • TNNI3K activity may be inhibited in mammalian cardiac tissue by administering to a patient in need thereof, an effective amount a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention may be particularly useful for treatment of TNNI3K-mediated diseases or disorders, specifically by inhibition of TNNI3K activity, where such diseases or disorders are selected from heart failure, particularly congestive heart failure; cardiac hypertrophy; and heart failure or congestive heart failure resulting from cardiac hypertrophy.
  • diseases or disorders are selected from heart failure, particularly congestive heart failure; cardiac hypertrophy; and heart failure or congestive heart failure resulting from cardiac hypertrophy.
  • the compounds of this invention may also be useful for the treatment of heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.
  • a therapeutically "effective amount” is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to modulate or inhibit the activity of TNNI3K such that a disease condition which is mediated by that activity is reduced, allew ' ated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC 5 o), efficacy (EC 5 o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the particular compound e.g., the potency (pXC 5 o), efficacy (EC 5 o), and the biological half-life of the particular compound
  • disease condition and its severity e.g., the identity of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by TNNI3K.
  • the methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.
  • the compounds of Formula I of this invention may be useful for the treatment of heart failure, particularly congestive heart failure.
  • the compounds of Formula I of this invention may be useful for the treatment of cardiac hypertrophy, and heart failure or congestive heart failure resulting from cardiac hypertrophy, myocardial ischemia or myocardial infarction.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Treatment of TNNI3K-mediated disease conditions may be achieved using the compounds of this invention as a monotherapy, or in dual or multiple combination therapy, such as in combination with other cardiovascular agents, for example, in combination with one or more of the following agents: a beta-blocker, an ACE inhibitor, an angiotensin receptor blocker (ARB), a calcium channel blocker, a diuretic, a renin inhibitor, a centrally acting antihypertensive, a dual ACE/NEP inhibitor, an aldosterone synthase inhibitor, and an aldosterone-receptor antagonist, which are administered in effective amounts as is known in the art.
  • a beta-blocker an ACE inhibitor
  • ARB angiotensin receptor blocker
  • beta blockers examples include timolol (such as BlocardenTM), carteolol (such as CartrolTM), carvedilol (such as CoregTM), nadolol (such as CorgardTM), propanolol (such as Innopran XLTM), betaxolol (such as KerloneTM), penbutolol (such as LevatolTM), metoprolol (such as Lopressort M and Toprol-XLTM), atenolol (such as TenorminTM), pindolol (such as ViskenTM), bisoprolol, bucindolol, esmolol, acebutolol, labetalol, nebivolol, celiprolol, sotalol, and oxprenolol.
  • timolol such as BlocardenTM
  • carteolol such as CartrolTM
  • carvedilol such as Coreg
  • ACE inhibitors examples include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril.
  • Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril.
  • angiotensin receptor blockers examples include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan.
  • suitable calcium channel blockers include dihydropyridines (DHPs) and non-DHPs. Suitable DHPs include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine,
  • Suitable non-DHPs are flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verampimil, and their pharmaceutically acceptable salts.
  • a suitable diuretic is a thiazide derivative selected from amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon.
  • a suitable renin inhibitor is aliskiren.
  • Suitable centrally acting antiphypertensives include clonidine, guanabenz, guanfacine and methyldopa.
  • suitable dual ACE/NEP inhibitors include omapatrilat, fasidotril, and fasidotrilat.
  • suitable aldosterone synthase inhibitors include anastrozole, fadrozole, and exemestane.
  • suitable aldosterone-receptor antagonists include spironolactone and eplerenone.
  • a compound of the invention may be employed alone, in combination with one or more other compounds of the invention or in combination with other therapeutic methods or agents.
  • combination with other chemotherapeutic, biologic, hormonal, antibody and supportive care agents is envisaged as well as combination with surgical therapy and radiotherapy.
  • Supportive care agents include analgesics, anti-emetics and agents used to treat heamatologic side effects such as neutropenia. Analgesics are well known in the art.
  • Anti-emetics include but are not limited to 5HT 3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like; prochlorperazine; metaclopromide; diphenhydramine; promethazine; dexamethasone; lorazepam; haloperidol; dronabinol; olanzapine; and neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopitant administered alone or in various combinations.
  • 5HT 3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like
  • prochlorperazine metaclopromide
  • diphenhydramine promethazine
  • dexamethasone dexamethasone
  • lorazepam haloperidol
  • dronabinol olanzapine
  • neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopi
  • chemotherapeutic refers to any chemical agent having a therapeutic effect on the subject to which it is administered.
  • “Chemotherapeutic” agents include but are not limited to anti-neoplastic agents.
  • anti-neoplastic agents include both cytotoxic and cytostatic agents including biological, immunological and vaccine therapies.
  • Combination therapies according to the invention thus comprise the administration of at least one compound of the invention and the use of at least one other treatment method.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and surgical therapy.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and radiotherapy.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and at least one supportive care agent (e.g., at least one anti-emetic agent).
  • combination therapies according to the present invention comprise the administration of at least one compound of the invention and at least one other chemotherapeutic agent.
  • the invention comprises the administration of at least one compound of the invention and at least one anti-neoplastic agent.
  • the present invention provides the methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one chemotherapeutic agent.
  • the chemotherapeutic agent is an anti-neoplastic agent.
  • the invention provides a pharmaceutical composition as described above further comprising at least one other chemotherapeutic agent, more particularly, the chemotherapeutic agent is an antineoplastic agent.
  • the invention also provides methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one supportive care agent (e.g., anti-emetic agent).
  • the compounds of the invention and at least one additional anti-neoplastic or supportive care therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination.
  • the administration of a compound of the invention with one or more other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in one unitary
  • composition including both or all compounds or two or more separate pharmaceutical compositions each including one or more of the compounds.
  • the components of the combination may be administered separately in a sequential manner wherein one active ingredient is administered first and the other(s) second or vice versa. Such sequential administration may be close in time or remote in time.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. The appropriate dose of the compound(s) of the invention and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.
  • any chemotherapeutic agent that has activity against a susceptible neoplasm being treated may be utilized in combination with the compounds of the invention, provided that the particular agent is clinically compatible with therapy employing a compound of the invention.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to: alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents, topoisomerase I and II inhibitors, hormones and hormonal analogues; retinoids, signal transduction pathway inhibitors including inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or other kinase inhibitors; cyclin dependent kinase inhibitors; antisense therapies and
  • immunotherapeutic agents including monoclonals, vaccines or other biological agents.
  • Alkylating agents are non-phase specific anti-neoplastic agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death. Alkylating agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • alkylating agents include but are not limited to nitrogen mustards such as cyclophosphamides, temozolamide, melphalan, and chlorambucil; oxazaphosphor-ines; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; triazenes such as dacarbazine; and platinum
  • coordination complexes such as cisplatin, oxaliplatin and carboplatin.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. The end result of discontinuing S phase is cell death.
  • Antimetabolite neoplastic agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • antimetabolite anti-neoplastic agents include but are not limited to purine and pyrimidine analogues and anti-folate compounds, and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mecaptopurine and thioguanine.
  • purine and pyrimidine analogues and anti-folate compounds and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mecaptopurine and thioguanine.
  • Antitumor antibiotic agents are non-phase specific agents, which bind to or intercalate with DNA. Typically, such action disrupts ordinary function of the nucleic acids, leading to cell death. Antitumor antibiotics may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antitumor antibiotic agents include, but are not limited to, actinomycins such as dactinomycin; anthracyclines such as daunorubicin, doxorubicin, idarubicin, epirubicin and mitoxantrone; mitomycin C and bleomycins.
  • Antimicrotubule or antimitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Antimitotic agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antimitotic agents include, but are not limited to, diterpenoids, vinca alkaloids, polo-like kinase (PIk) inhibitors and CenpE inhibitors. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vindesine and vinorelbine. PIk inhibitors are discussed further below.
  • Topoisomerase inhibitors include inhibitors of Topoisomerase II and inhibitors of Topoisomerase I.
  • Topoisomerase II inhibitors such as epipodophyllotoxins, are antineoplastic agents derived from the mandrake plant, that typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, causing DNA strand breaks. The strand breaks accumulate and cell death follows.
  • Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Camptothecins including camptothecin and camptothecin derivatives, are available or under development as Topoisomerase I inhibitors.
  • Examples of camptothecins include, but are not limited to amsacrine, irinotecan, topotecan, and the various optical forms of 7- (4-methylpiperazino-methylene)-10, 1 1-ethylenedioxy-20-camptothecin.
  • Topoisomerase inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • Antitumor hormones and hormonal analogues may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to antiestrogens, such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene and droloxifene; anti-androgens; such as flutamide, nilutamide, bicalutamide and cyproterone acetate;
  • adrenocorticosteroids such as prednisone and prednisolone
  • aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane
  • progestrins such as megestrol acetate; 5a-reductase inhibitors such as finasteride and dutasteride; and gonadotropin-releasing hormones (GnRH) and analogues thereof, such as Leutinizing Hormone-releasing Hormone (LHRH) agonists and antagonists such as goserelin luprolide, leuprorelin and buserelin.
  • progestrins such as megestrol acetate
  • 5a-reductase inhibitors such as finasteride and dutasteride
  • gonadotropin-releasing hormones (GnRH) and analogues thereof such as Leutinizing Hormone-releasing Hormone (LHRH) agonists and antagonists such as goserelin luprolide, leuprorelin and buserelin.
  • LHRH Leutinizing Hormone-releasing Hormone
  • Retinoid(s) are compounds that bind to and activate at least one retinoic acid receptor selected from RARa, RAR3, and RARy and/or compounds that bind to and activate at least one of RARa, RAR3, and RARy and also at least one retinoic X receptor (RXR), including RXRa, RXR3, and RXRy.
  • RXR retinoic X receptor
  • Retinoids for use in the present invention typically have affinity for RAR, and particularly for RARa and/or RAR3.
  • certain synthetic retinoids, such as 9-cis-retinoic acid also have affinity for both RAR and RXR.
  • the retinoid has affinity for RARa (and RARa agonist).
  • retinoids examples include: retinoic acid; all-trans-retinoic acid (“ATRA” also known as “tretinoin”); tamibarotene (“Am80”); 9-cis-retinoic acid ((2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6- trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic Acid) (also known as “9-cis-Tretinoin”) (available from Sigma); Isotretinoin ((2Z,4£,6£,8£)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid) (also known as "13-cis-retinoic acid”)
  • Signal transduction pathway inhibitors are those inhibitors which block or inhibit a chemical process which evokes an intracellular change. As used herein these changes include, but are not limited to, cell proliferation or differentiation or survival.
  • Signal transduction pathway inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases, myoinositol signaling, and Ras oncogenes. Signal transduction pathway inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinase inhibitors which may be combined with the compounds of the invention include those involved in the regulation of cell growth, which receptor tyrosine kinases are sometimes referred to as "growth factor receptors."
  • growth factor receptor inhibitors include but are not limited to inhibitors of: insulin growth factor receptors (IGF- 1 R, IR and IRR); epidermal growth factor family receptors (EGFR, ErbB2, and ErbB4); platelet derived growth factor receptors (PDGFRs), vascular endothelial growth factor receptors (VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), macrophage colony stimulating factor (c-fms), c-kit, c- met, fibroblast growth factor receptors (FGFRs), hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB, and TrkC), ephrin (E
  • Trastuzumab (Herceptin ® ) is an example of an anti-erbB2 antibody inhibitor of growth factor function.
  • An anti-erbB1 antibody inhibitor of growth factor function is cetuximab (ErbituxTM, C225).
  • Bevacizumab (Avastin ® ) is an example of a monoclonal antibody directed against VEGFR.
  • small molecule inhibitors of epidermal growth factor receptors include but are not limited to lapatinib (Tykerb ® ) and erlotinib (Tarceva ® ).
  • Imatinib (Gleevec ® ) is one example of a PDGFR inhibitor.
  • VEGFR inhibitors include pazopanib (VotrientTM), ZD6474, AZD2171 , PTK787, sunitinib and sorafenib.
  • the invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with an EGFR or ErbB inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with lapatinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with trastuzumab. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with erlotinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with gefitinib.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a VEGFR inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with pazopanib.
  • Tyrosine kinases that are not transmembrane growth factor receptor kinases are termed non-receptor, or intracellular tyrosine kinases.
  • Inhibitors of non-receptor tyrosine kinases are sometimes referred to as "anti-metastatic agents" and are useful in the present invention.
  • Targets or potential targets of anti-metastatic agents include, but are not limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl and Bcr-Abl), FAK (focal adhesion kinase) and Bruton's tyrosine kinase (BTK).
  • Non-receptor kinases and agents, which inhibit non-receptor tyrosine kinase function are described in Sinha, S. and Corey, S.J., J. Hematother. Stem Cell Res. (1999) 8 465-80; and Bolen, J.B. and Brugge, J.S., Annu. Rev. of Immunol. (1997) 15 371-404.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, but not limited to, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • Src inhibitors include, but are not limited to, dasatinib and BMS-354825 (J. Med. Chem. (2004) 47 6658-6661 ).
  • Inhibitors of serine/threonine kinases may also be used in combination with the compounds of the invention in any of the compositions and methods described above.
  • Examples of serine/threonine kinase inhibitors that may also be used in combination with a compound of the present invention include, but are not limited to, polo-like kinase inhibitors (Plk family e.g., Plk1 , Plk2, and Plk3), which play critical roles in regulating processes in the cell cycle including the entry into and the exit from mitosis; MAP kinase cascade blockers, which include other Ras/Raf kinase inhibitors, mitogen or extracellular regulated kinases (MEKs), and extracellular regulated kinases (ERKs); Aurora kinase inhibitors (including inhibitors of Aurora A and Aurora B); protein kinase C (PKC) family member blockers, including inhibitors of PKC subtypes (alpha, beta, gamma,
  • PKB/Akt kinase family inhibitors and inhibitors of TGF-beta receptor kinases.
  • Examples of PIk inhibitors are described in PCT Publication No. WO04/014899 and WO07/03036.
  • Other examples of serine/threonine kinase inhibitors are known in the art.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a PIk inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with 5- ⁇ 6- [(4-methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1 -yl ⁇ -3- ⁇ (1 R)-1-[2- (trifluoromethyl)phenyl]ethoxy ⁇ thiophene-2-carboxamide.
  • Urokinase also referred to as urokinase-type Plasminogen Activator (uPA) is a serine protease. Activation of the serine protease plasmin triggers a proteolysis cascade which is involved in thrombolysis or extracellular matrix degradation. Elevated expression of urokinase and several other components of the plasminogen activation system have been correlated with tumor malignancy including several aspects of cancer biology such as cell adhesion, migration and cellular mitotic pathways as well. Inhibitors of urokinase expression may be used in combination with the compounds of the invention in the compositions and methods described above.
  • Inhibitors of Ras oncogene may also be useful in combination with the compounds of the present invention.
  • Such inhibitors include, but are not limited to, inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti- sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block Ras activation in cells containing mutant Ras, thereby acting as antiproliferative agents.
  • Inhibitors of kinases involved in the IGF-1 R signaling axis may also be useful in combination with the compounds of the present invention.
  • Such inhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K, AKT and MEK, and 14.3.3 signaling inhibitors. Examples of AKT inhibitors are described in PCT Publication No. WO 2007/058850, published 24 May 2007 which corresponds to PCT Application No. PCT/US2006/043513, filed 9 Nov 2006.
  • AKT inhibitor disclosed therein is 4-(2-(4-amino-1 ,2,5- oxadiazol-3-yl)-1 -ethyl-7- ⁇ [(3S)-3-piperidinylmethyl]oxy ⁇ -1 /-/-imidazo[4,5-c]pyridin-4-yl)-2- methyl-3-butyn-2-ol.
  • Cell cycle signaling inhibitors including inhibitors of cyclin dependent kinases (CDKs) are also useful in combination with the compounds of the invention in the compositions and methods described above. Examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania G. R. et al., Exp. Opin. Ther. Patents (2000) 10 215-230.
  • Receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related to VEGFR and TIE-2 are discussed above in regard to signal transduction inhibitors (both are receptor tyrosine kinases).
  • Other inhibitors may be used in combination with the compounds of the invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v beta 3 ) that inhibit angiogenesis; endostatin and angiostatin (non-rtK) may also prove useful in combination with the compounds of the invention.
  • VEGFR antibody is bevacizumab (Avastin ® ).
  • Inhibitors of phosphatidyl inositol-3-OH kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in combination with the present invention.
  • myoinositol signaling inhibitors such as phospholipase C blockers and myoinositol analogues.
  • siRNA, RNAi, locked nucleic acid polynucleotides, and antisense therapies may also be used in combination with the compounds of the invention.
  • antisense therapies include those directed towards the targets described above such as ISIS 2503 and gene therapy approaches such as those using thymidine kinase or cytosine deaminase.Agents used in immunotherapeutic regimens may also be useful in
  • Immunotherapeutic regimens include ex-vivo and in-vivo approaches to increasing immunogenicity of patient tumor cells such as transfection with cytokines (eg. IL-2, IL-4, GMCFS and MCFS), approaches to increase T-cell activity, approaches with transfected immune cells and approaches with anti- idiotypic antibodies.
  • cytokines eg. IL-2, IL-4, GMCFS and MCFS
  • approaches to increase T-cell activity approaches with transfected immune cells and approaches with anti- idiotypic antibodies.
  • Another potentially useful immunotherapeutic regimen is monoclonal antibodies with wild-type Fc receptors that may illicit an immune response in the host (e.g., IGF-1 R monoclonal antibodies).
  • Bcl-2 antisense oligonucleotides may also be used in combination with the compounds of the invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of Bcl-2 has therefore been linked to chemoresistance.
  • EGF epidermal growth factor
  • mcl-1 mcl-1 . Therefore, strategies designed to downregulate the expression of Bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide.
  • the invention further includes the use of compounds of the invention as an active therapeutic substance, in particular in the treatment of diseases mediated by TNNI3K or B-Raf kinase.
  • the invention includes the use of compounds of the invention in the treatment of heart failure, particularly congestive heart failure; cardiac hypertrophy; heart failure or congestive heart failure resulting from cardiac hypertrophy; and heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.
  • the invention includes the use of compounds of the invention in the treatment of susceptible neoplasms.
  • Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer;
  • central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and
  • erythroleukemia hepatocellular carcinoma
  • lung cancer including small cell lung cancer and non-small cell lung cancer
  • ovarian cancer endometrial cancer
  • pancreatic cancer pituitary adenoma
  • prostate cancer renal cancer
  • sarcoma skin cancers including melanomas
  • thyroid cancers include melanomas
  • the invention includes the use of compounds of the invention in the manufacture of a medicament for use in the treatment of the above disease and disorders.
  • the compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof).
  • the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a material, composition or vehicle involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically-acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • the compounds of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants,
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • KOf-Bu (1 .908 g, 17.00 mmol) was added to a dark orange solution of 6-bromo-4- chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c ]pyrimidine (1 .267 g, 3.4 mmol) in THF (34 mL) in a 250 mL round bottom flask. The orange suspension was then stirred at rt under nitrogen for 3.5 h. The reaction mixture was diluted with sat. aq. NaHC0 3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo.
  • deazapurine was prepared from 5-bromo-4-chloro-1 /-/-pyrrolo[2,3- c/]pyrimidine using the indicated alkyl halide and procedures analogous to those described in Preparation 16:
  • reaction material was purified by flash column chromatography (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ). The resulting solid was triturated with MeOH to afford the title compound (130 mg, 66.4%) as an off-white solid.
  • reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent to afford the title compound (1 .5 g, 74.8%) as an off white solid.
  • reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH 4 OH / 9% MeOH / 90% CHCIs) / CHCI3 as eluent to afford the title compound (98 mg, 31.6%) as an off white solid.
  • reaction materials were concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent.
  • the resulting solid was triturated with CH 2 CI 2 to afford the title compound (1 12 mg, 45%) as a light tan solid.
  • the organic portion was concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent.
  • the resulting solid was triturated with CH 2 CI 2 to afford 50 mg of an off-white solid.
  • the solid was further purified by reverse phase HPLC using 10-80% CH 3 CN/water (0.1 % TFA mobile phase).
  • the resulting TFA salt was neutralized with aq. NaHC0 3 , then extracted into EtOAc.
  • the organic extract was dried over Na 2 S0 4 and concentrated to afford the title compound (40 mg, 27%) as an off-white solid.
  • reaction materials were concentrated onto Celite ® and purified by flash column chromatography using 0-60% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent to afford the title compound (42 mg, 1 1 %) as an off-white solid.
  • the organic layer was concentrated onto Celite ® and purified by flash column chromatography using 30-80% (1 % NH 4 OH / 9% MeOH / 90% CHCI 3 ) / CHCI 3 as eluent.
  • the resulting solid was triturated with CH 2 CI 2 , followed by further purification by reverse phase HPLC using 10-50 CH 3 CN/water (0.1 % TFA in mobile phase).
  • the resulting TFA salt was basified with 1 % NH 4 OH / 9% MeOH / 90% CHCI 3 and concentrated down to dryness. The residue was triturated with water to afford the title compound (80 mg, 39%) as light pink solid.
  • a heterogeneous mixture of AgOTf (0.70 g, 2.72 mmol), 2-chloropurine (0.35 g, 2.26 mmol) and 3-amino-4-(dimethylamino)-/V-methylbenzenesulfonamide (0.62 g, 2.72 mmol) in 1 ,4-dioxane (22 mL) was stirred at 100 °C in a sealed high pressure vessel for 18 h. A dark grey precipitate formed which contained most of the product.
  • the reaction mixture was concentrated in vacuo, the solid residue dispersed into silica gel, and purified by flash column chromatography using 0-10% 10:1 :90 MeOH:NH 4 OH:EtOAc in EtOAc as eluent.
  • the desired fractions were combined and concentrated in vacuo.
  • the residue was dissolved in a small amount of CH 2 CI 2 and MeOH and a white precipitate came out of solution upon concentration. This precipitate was collected to afford the title compound (350mg, 44.5%) as an off-white solid.
  • a heterogeneous mixture of AgOTf (0.70 g, 2.72 mmol), 2-chloropurine (0.35 g, 2.26 mmol) and 3-amino-/V-methyl-4-(methyloxy)benzenesulfonamide (0.60 g, 2.77 mmol) in 1 ,4-dioxane (1 1 ml.) was stirred at 100 °C in a sealed high pressure vessel for 18 h.
  • the reaction mixture was filtered through a pad of Celite ® , washing with MeOH.
  • the filtrate was concentrated and purified by flash column chromatography, eluting with 10:1 :90 MeOH:NH 4 OH:CHCI 3 .
  • the reaction vessel was sealed and heated at 100 °C for 20 h.
  • the mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI 3 containing 0.1 % ⁇ 3 ⁇ 2 0) to afford a yellow solid which was triturated with CH 2 CI 2 to afford the title compound (133 mg, 48%) as a light yellow solid.

Abstract

Disclosed are compounds having the Formula (I), wherein X, Y, Z, R1, R2 and R3 are as defined herein, and methods of making and using the same.

Description

COMPOUNDS AND METHODS
FIELD OF THE INVENTION
The present invention relates to compounds that inhibit TNNI3K and B-Raf kinase and methods of making and using the same. Specifically, the present invention relates to anilino-deazapurines, anilino-purines, and anilino-pyrazolopyrimidines as TNNI3K and B-Raf kinase inhibitors.
BACKGROUND OF THE INVENTION
Cardiac troponin l-interacting kinase (TNNI3K), also known as CARK (for cardiac ankyrin repeat kinase), is a protein kinase that exhibits highly selective expression for cardiac tissues and has been shown to interact with components of the sarcomere, including troponin I (Zhao, Y. et al., J. Mol. Med., 2003, 81, 297-304; Feng, Y. et al., Gen. Physiol. Biophys., 2007, 26, 104-109; Wang, H. et al., J. Cell. Mol. Med., 2008, 12, 304- 315). Although substrates for TNNI3K have not been identified to date, recent reports suggest that this protein does play a role in the development of pressure-induced cardiomyocyte hypertrophy and contractile dysfunction (Wheeler, F. C. et al., Mamm. Genome, 2005, 16, 414-423; Wang, X. et al., "TNNI3K, a cardiac-specific kinase, promotes cardiac hypertrophy in vivo", Poster presentation at the 2006 Scientific Sessions of the American Heart Association, Chicago, IL, Wheeler, F. C. et al., PLos Genet, 2009, 5(9), e1000647; and Pu, W.T., PLos Genet, 2009, 5(9), e1000643). Inhibition of the kinase activity of TNNI3K may disrupt these signaling pathways, and enable the mitigation and/or reversal of cardiac hypertrophy seen in patients with progressively worsening heart failure.
In response to mechanical, neurohormonal, and genetic stimuli, the heart will undergo hypertrophy, or muscle growth and remodeling, in order to maintain sufficient cardiac output to meet tissue oxygen demands. While these structural changes are initially seen as compensatory, sustained dysregulation of hypertrophic signaling can lead to heart failure, the pathophysiological state in which the heart can no longer adequately function as a pump (Mudd, J. O. and Kass, D. A., Nature, 2008, 451, 919-928).
Prevention or reversal of pathological cardiac hypertrophy has the potential to delay or prevent the development of congestive heart failure (McKinsey, T. A. and Kass, D. A., Nat. Rev. Drug Discov., 2007, 6, 617-635; Kaye, D. M. and Krum, H., Nat. Rev. Drug Discov., 2007, 6, 127-139).
Heart failure is responsible for a reduced quality of life and premature death in a significant proportion of sufferers, and is characterized by impaired cardiac function either due to reduced pump function (systolic dysfunction) or reduced filling (diastolic
dysfunction). Congestive heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. The prevalence of heart failure is anticipated to increase with ageing populations, prompting a need for new and improved methods of treating heart failure.
Both receptor tyrosine kinases and serine/threonine kinases have been implicated in cellular signaling pathways that control cell function, division, growth, differentiation, and death (apoptosis) through reversible phosphorylation of the hydroxyl groups of tyrosine or serine and threonine residues, respectively, in proteins. In signal transduction, for example, extracellular signals are transduced via membrane receptor activation, with amplification and propagation using a complex choreography of cascades of protein phosphorylation, and protein dephosphorylation events to avoid uncontrolled signaling. These signaling pathways are highly regulated, often by complex and intermeshed kinase pathways where each kinase may itself be regulated by one or more other kinases and protein phosphatases. The biological importance of these finely tuned systems is such that a variety of cell proliferative disorders have been linked to defects in one or more of the various cell signaling pathways mediated by tyrosine or serine/threonine kinases.
Receptor tyrosine kinases (rtKs) catalyze phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which govern cell growth, proliferation and differentiation. Downstream of the several rtKs lie several signaling pathways, among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases.
These kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2. This signaling pathway, also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals. The ultimate function of this is to link receptor activity at the cell membrane with modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival. Mutations in various Ras GTPases and the B-Raf kinase have been identified that can lead to sustained and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival. As a consequence of this, these mutations have been strongly linked with the establishment, development, and progression of a wide range of human cancers. The biological role of the Raf kinases, and specifically that of B-Raf, in signal transduction is described in Davies, H., et al., Nature (2002) 9 1-6; Garnett, M.J. & Marais, R., Cancer Cell (2004) 6 313-319; Zebisch, A. & Troppmair, J., Cell. Mol. Life Sci. (2006) 63 1314-1330; Midgley, R.S. & Kerr, D.J., Crit. Rev. Onc/Hematol. (2002) 44 109- 120; Smith, R.A., et al., Curr. Top. Med. Chem. (2006) 6 1071-1089; and Downward, J., Nat. Rev. Cancer (2003) 3 1 1-22.
Naturally occurring mutations of the B-Raf kinase that activate MAPK pathway signaling have been found in a large percentage of human melanomas (Davies (2002) supra) and thyroid cancers (Cohen et al., J. Nat. Cancer Inst. (2003) 95 625-627 and Kimura et al., Cancer Res. (2003) 63 1454-1457), as well as at lower, but still significant, frequencies in the following:
Barret's adenocarcinoma (Garnett et al., Cancer Cell (2004) 6 313-319 and
Sommerer et al., Oncogene (2004) 23 554-558),
billiary tract carcinomas (Zebisch et al., Cell. Mol. Life Sci. (2006) 63 1314-1330), breast cancer (Davies (2002) supra),
cervical cancer (Moreno-Bueno et al., Clin. Cancer Res. (2006) 12 3865-3866), cholangiocarcinoma (Tannapfel et al., Gut (2003) 52 706-712),
central nervous system tumors including primary CNS tumors such as
glioblastomas, astrocytomas and ependymomas (Knobbe et al., Acta Neuropathol. (Berl.) (2004) 108 467-470, Davies (2002) supra, and Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system),
colorectal cancer, including large intestinal colon carcinoma (Yuen et al., Cancer Res. (2002) 62 6451 -6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006), 63 1314-1330),
gastric cancer (Lee et al., Oncogene (2003) 22 6942-6945),
carcinoma of the head and neck including squamous cell carcinoma of the head and neck (Cohen et al., J. Nat. Cancer Inst. (2003) 95 625-627 and Weber et al.,
Oncogene (2003) 22 4757-4759),
hematologic cancers including leukemias (Garnett et al., Cancer Cell (2004) supra), particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al., Leukemia (2005) 19 310-312), acute myelogenous leukemia (AML) (Lee et al., Leukemia (2004) 18 170-172, and Christiansen et al., Leukemia (2005) 19 2232-2240), myelodysplastic syndromes (Christiansen et al., Leukemia (2005) supra) and chronic myelogenous leukemia (Mizuchi et al., Biochem. Biophys. Res. Commun. (2005) 326 645-651 ); Hodgkin's lymphoma (Figl et al., Arch. Dermatol. (2007) 143 495-499), non- Hodgkin's lymphoma (Lee et al., Br. J. Cancer (2003) 89 1958-1960), megakaryoblastic leukemia (Eychene et al., Oncogene (1995) 10 1 159-1 165) and multiple myeloma (Ng et al., Br. J. Haematol. (2003) 123 637-645),
hepatocellular carcinoma (Garnett et al., Cancer Cell (2004) 6 313-319), lung cancer (Brose et al., Cancer Res. (2002) 62 6997-7000, Cohen et al., J. Nat. Cancer Inst. (2003) supra and Davies (2002) supra), including small cell lung cancer
(Pardo et al., EMBO J. (2006) 25 3078-3088) and non-small cell lung cancer (Davies
(2002) supra),
ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203 617-619 and Davies (2002) supra), endometrial cancer (Garnett et al., Cancer Cell (2004) supra, and Moreno- Bueno et al., Clin. Cancer Res. (2006) supra),
pancreatic cancer (Ishimura et al., Cancer Lett. (2003) 199 169-173),
pituitary adenoma (De Martino et al., J. Endocrinol. Invest. (2007) 30 RC1-3), prostate cancer (Cho et al., Int. J. Cancer (2006) 1 19 1858-1862),
renal cancer (Nagy et al., Int. J. Cancer (2003) 106 980-981 ),
sarcoma (Davies (2002) supra), and
skin cancers (Rodriguez-Viciana et al., Science (2006) 31 1 1287-1290 and Davies (2002) supra).
Overexpression of c-Raf has been linked to AML (Zebisch et al., Cancer Res. (2006) 66 3401-3408, and Zebisch {Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et la., Cell. Mol. Life Sci. (2006).
By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A.J., et al., (2006) Cancer Res. 66 1 1 100-1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases will be useful for the treatment of such cancers or other condition associated with Raf kinase.
Mutation of B-Raf has also been implicated in other conditions, including cardio- facio cutaneous syndrome (Rodriguez-Viciana et al., Science (2006) 31 1 1287-1290) and polycystic kidney disease (Nagao et al., Kidney Int. (2003) 63 427-437). SUMMARY OF THE INVENTION
The invention is directed to novel anilino-deazapurines, anilino-purines, and anilino- pyrazolopyrimidines. Specifically, the invention is directed to a compound according to Formula I:
Figure imgf000006_0001
wherein:
R1 is (Ci-C4)alkyl;
X is N or CH;
Y is N or CR4;
Z is N or CR4;
R2 is H, halogen, (d-C8)alkyl, (C C8)haloalkyl, hydroxy(C C8)alkyl-,
(Ci-C8)alkylthio-, (C C8)haloalkylthio-, (C3-C8)cycloalkylthio-, aryl, heteroaryl, -N(Ra)(Rb), or -ORc; wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC6)alkyl, (Ci-C4)haloalkyl, hydroxyl, (Ci-C6)alkoxy,
(Ci-C4)haloalkoxy, hydroxy(C C4)alkyl-, (C C4)alkoxy(Ci-C4)alkyl-, -N(Ra)(Rb), cyano, -CON(Ra)(Rb), -C02Rc, -CO(Ci-C4)alkyl, -S02N(Ra)(Rb), -S02(C C4)alkyl,
-NHCO(Ci-C4)alkyl, or -NHS02(Ci-C4)alkyl;
each Ra is (C1-C4)alkyl, which is optionally substituted one to three times, independently, by halogen, hydroxyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino,
((d-d)alkyl)((d-C6)alkyl)amino, -C02H, -C02(C C6)alkyl, -CONH2, -CONH(d-C6)alkyl, -CON((C1-d)alkyl)((C1-d)alkyl), or aryl, wherein said aryl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)alkyl, (d-d)haloalkyl,
(d-d)alkoxy, (d-d)haloalkoxy, hydroxy(d-d)alkyl-, amino, (d-d)alkylamino, or ((Ci-d)alkyl)((Ci-d)alkyl)amino, -CONH2, -CONH(d-d)alkyl,
-CON((Ci-d)alkyl)((Ci-d)alkyl), -CO(d-d)alkyl, -C02(d-d)alkyl, -S02NH2,
-S02NH(Ci-d)alkyl, -S02N((Ci-d)alkyl)((C d)alkyl), -S02(d-d)alkyl,
-NHCO(Ci-d)alkyl, or -NHS02(d-C4)alkyl;
each Rb is H or (d-d)alkyl;
or Ra and Rb taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino,
(C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, hydroxyl, hydroxy(C1-C4)alkyl-, oxo, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, (Ci-C4)alkoxy(CrC4)alkyl, or cyano;
R3 is H;
or R2 and R3 taken together with atoms through which they are connected form a non-aromatic 5-membered ring, which may be unsubstituted or substituted with one or two substituents independently selected from (Ci-C4)alkyl, (Ci-C4)haloalkyl,
hydroxy(Ci-C4)alkyl-, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, (Ci-C4)alkylthio-,
(Ci-C4)haloalkylthio-; -C02R , -(C C4)alkyl-C02R , -CORf , -CON(Rd)(Re), and
-(Ci-C4)alkyl-CON(Rd)(Re);
each R4 is independently selected from H, halogen, cyano, (Ci-C8)alkyl,
(C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C C4)haloalkyl, (C C4)alkoxy,
(Ci-C4)haloalkoxy, (C C4)alkylthio-, (C C4)haloalkylthio-, -C02R , -(C C4)alkyl-C02R , -CORf , -CON(Rd)(Re), -(Ci-C4)alkyl-CON(Rd)(Re), heterocycloalkyl, aryl, and heteroaryl; wherein the aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (Ci-C4)alkyl, (C3-C6)cycloalkyl, (Ci-C4)haloalkyl, cyano, nitro, oxo,-ORc, -(d-C4)alkyl-ORc, -SRC, -(C C4)alkyl-SRc, -CO(d-C4)alkyl, -(d-d)alkyl- CO(d-C4)alkyl, -CONHRd, -CON(Rd)(Re), -(C d)alkyl-CON(Rd)(Re), -S02(d-d)alkyl, -(d-d)alkyl-S02(d-d)alkyl, -S02NHRd, -S02N(Rd)(Re), -(d-d)alkyl-S02N(Rd)(Re), -NHRd, -N(Rd)(Re), -(d-d)alkyl-NHRd, -(C d)alkyl-N(Rd)(Re), -C02Rf, -(d-d)alkyl- C02Rf, -NHS02(Ci-d)alkyl, -(d-d)alkyl-NHS02(Ci-d)alkyl, -NHCO(d-d)alkyl, -(d-C4)alkylNHCO(d-C4)alkyl, -NHCOO(d-d)alkylphenyl,
-(Ci-d)alkylNHCOO(Ci-d)alkylphenyl, aryl, or heteroaryl;
wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (d-C6)alkyl, (C3-C6)cycloalkyl, (d-d)haloalkyl, cyano, nitro, -ORc, -N(Rd)(Re), -CON(Rd)(Re), -C02Rc, -CO(d-C4)alkyl, -S02N(Rd)(Re),
-S02(Ci-d)alkyl,-NHCO(Ci-d)alkyl, or -NHS02(Ci-d)alkyl,
Rc is H, (Ci-C6)alkyl, (d-C8)cycloalkyl, or -(d-C4)alkyl(C3-C8)cycloalkyl, wherein said (d-C6)alkyl or (C3-C8)cycloalkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)haloalkyl, (d-d)alkoxy, amino,
(d-C4)alkylamino, ((Ci-d)alkyl)((C d)alkyl)amino, -C02H, -C02(d-C4)alkyl, -CONH2, -CONH(Ci-d)alkyl, -CON((Ci-d)alkyl)((C d)alkyl), heterocycloalkyl, or aryl, wherein said aryl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)alkyl, (d-d)haloalkyl, (d-d)alkoxy, (d-d)haloalkoxy, hydroxy(d-d)alkyl-, amino, (C1-d)alkylamino, or ((C1-d)alkyl)((C1-d)alkyl)amino, -CONH2, -CONH(Ci-C4)alkyl, -CON((C1-C4)alkyl)((C1-C4)alkyl), -CO(C C4)alkyl, -C02(C C4)alkyl, -S02NH2, -S02NH(C C4)alkyl, -S02N((C1-C4)alkyl)((C1-C4)alkyl), -S02(C C4)alkyl, -NHCO(d-C4)alkyl, or -NHS02(d-C4)alkyl;
Rd is independently selected from H, (Ci-C )alkyl, aryl, heterocycloalkyi or heterocycloalkyl-(Ci-C2)alkyl, wherein said (Ci-C )alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (CrC )alkoxy, amino, (Ci-C )alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -C02H, -C02(C C4)alkyl, -CONH2, -CONH(Ci-C4)alkyl, or -CON((Ci-C )alkyl)((CrC )alkyl), and wherein any heterocycloalkyi is optionally substituted by (Ci-C )alkyl;
Re is (Ci-C4)alkyl;
or Rd and Re taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (Ci-C )alkyl, (Ci-C )haloalkyl, amino,
(Ci-C )alkylamino, ((Ci-C )alkyl)((Ci-C )alkyl)amino, hydroxyl, hydroxy(Ci-C )alkyl-, oxo, (Ci-C )alkoxy, (Ci-C )haloalkoxy, or (CrC )alkoxy(Ci-C )alkyl; and
R is H, (Ci-C )alkyl, cycloalkyl, 5-6-membered heterocycloalkyi, phenyl, or 5-6- membered heteroaryl, wherein said (C1-C4)alkyl, cycloalkyl, 5-6-membered
heterocycloalkyi, phenyl, or 5-6-membered heteroaryl is optionally substituted one to three times, independently, by (C1-C4)alkyl, hydroxyl, (CrC4)alkoxy, amino, (C1-C4)alkylamino, ((C C^alkylXid-C^alky amino;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The compounds of the invention are inhibitors of TNNI3K and can be useful for the treatment of cardiac diseases and disorders, particularly heart failure. The compounds of the invention are also inhibitors of B-Raf kinase and can be useful for the treatment of susceptible neoplasms.
This invention is directed to pharmaceutical compositions comprising a compound of the invention or a salt, particularly a pharmaceutical salt, thereof.
One embodiment of this invention is directed to methods of inhibiting TNNI3K and treatment of conditions associated therewith comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a salt thereof.
Another embodiment of this invention is directed to a method of treating a susceptible neoplasm in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a salt thereof.
Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system);
colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one or more of the substituents defined herein. Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, pentyl, and hexyl. The term "C1-C4" refers to an alkyl containing from 1 to 4 carbon atoms.
When the term "alkyl" is used in combination with other substituent groups, such as "haloalkyl", "hydroxyalkyl", or "alkoxyalkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
As used herein, the term "alkenyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon double bonds. Examples include ethenyl and propenyl.
As used herein, the term "alkynyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon triple bonds. Examples include ethynyl and propynyl.
As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(C3-C8)cycloalkyl" refers to a non-aromatic cyclic
hydrocarbon ring having from three to eight ring carbon atoms. Exemplary "(C3-C8)cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
"Alkoxy" means an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom. The term "(CrC4)alkoxy" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(d-C4)alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.
"Alkylthio-" means an alkyl radical containing the specified number of carbon atoms attached through a sulfur linking atom. The term "(CrC4)alkylthio-" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through a sulfur linking atom. Exemplary "(CrC4)alkylthio-" groups useful in the present invention include, but are not limited to, methylthio-, ethylthio-, n-propylthio-, isopropylthio-, n-butylthio-, s-butylthio-, and f-butylthio-.
"Cycloalkyloxy" and "cycloalkylthio" means a saturated carbocyclic ring containing
3-8 ring atoms attached through an oxygen or sulfur linking atom, respectively. Examples of "cycloalkyloxy" moieties include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"Aryl" represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be
unsubstituted or substituted by one or more substituents defined herein.
Generally, in the compounds of this invention, aryl is phenyl.
Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
"Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also
encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. Illustrative examples of heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8- naphthyridinyl, and pteridinyl.
Generally, the heteroaryl groups present in the compounds of this invention are 5-membered and/or 6-memebred monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
"Heterocycloalkyl" represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein. Illustrative examples of heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, hexahydro-1 H- 1 ,4-diazepinyl, azabicylo[3.2.1 ]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1 ]heptyl and 1 ,5,9-triazacyclododecyl.
Generally, in the compounds of this invention, heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3- dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, and hexahydro-1 /-/-1 ,4-diazepinyl.
Όχο" represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C=0).
The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH. As used herein, the term "compound(s) of the invention" means a compound of Formula I (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
As used herein, the term ""optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent(s) as defined. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. The alternative definitions for the various groups and substituent groups of Formula I provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions.
Suitably, R1 is (C1-C4)alkyl. In a specific embodiment of this invention, R1 is methyl or ethyl.
Suitably, X is N or CH. In a specific embodiment of this invention, X is CH.
Suitably, Y is N or CR4 and Z is N or CR4. In a specific embodiment of this invention, Y and Z are each independently CR4. Such compounds of the invention may be depicted according to Formula la:
Figure imgf000012_0001
In another specific embodiment of this invention, Y is CR4 and Z is N.
pounds of the invention may be depicted according to Formula lb:
Figure imgf000013_0001
In a further specific embodiment of this invention, Y is N and Z is CR4. Such compounds of the invention may be depicted according to Formula Ic:
Figure imgf000013_0002
Suitably, R2 is H, halogen, (C C8)alkyl, (d-C8)haloalkyl, hydroxy(C C8)alkyl-, (Ci-Ce)alkylthio-, (C C8)haloalkylthio-, (C3-C8)cycloalkylthio-, aryl, heteroaryl, -N(Ra)(Rb), or -ORc; wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC6)alkyl, (Ci-C4)haloalkyl, hydroxyl, (Ci-C6)alkoxy,
(Ci-C4)haloalkoxy, hydroxy(C C4)alkyl-, (C C4)alkoxy(Ci-C4)alkyl-, -N(Ra)(Rb), cyano, -CON(Ra)(Rb), -C02Rc, -CO(Ci-C4)alkyl, -S02N(Ra)(Rb), -S02(C C4)alkyl,
-NHCO(Ci-C4)alkyl, or -NHS02(Ci-C4)alkyl.
In another embodiment of this invention, R2 is H, F, CI, Br, (CrC6)alkyl,
(Ci-C6)haloalkyl, hydroxy(CrC6)alkyl-, hydroxyl, (CrC6)alkoxy, (CrC6)alkylthio-,
(Ci-C6)haloalkoxy, (C3-C8)cycloalkoxy, (C3-C8)cycloalkyl(CrC6)alkoxy, (Ci-C6)alkylamino, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino, (hydroxy(Ci-C6)alkyl)((Ci-C6)alkyl)amino,
((C1-C6)alkoxy(C1-C6)alkyl)((C1-C6)alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl; wherein said pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one to two times, independently, by halogen, (C1-C4)alkyl,
(C1-C4)haloalkyl, cyano, hydroxyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, hydroxy(C1-C4)alkyl-, (Ci-C4)alkoxy(CrC4)alkyl-, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino.
In a specific embodiment of this invention, R2 is H, F, CI, methyl, phenyl, 1-methyl- pyrazol-5-yl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, n-propoxy, 3,3,3-trifluoro-n-propoxy, n-butoxy, s-butoxy, 1-methyl-3,3,3-trifluoro-n-propoxy,
1 ,3-dimethylpropoxy, 3-methoxyphenylmethoxy, cyclohexylmethoxy, 2-cyclohexylethoxy, cyclopentyloxy, cyclohexyloxy, 4-trifluoromethylcyclohexyloxy, 4-methoxycyclohexyloxy, cycloheptyloxy, 2-(pyrrolidin-1 -yl)ethoxy, 2-(piperidin-1-yl)ethoxy, 2-(piperidin-4-yl)ethoxy, methylthio-, n-propylamino, 3-methoxyphenylmethylamino, dimethylamino,
(ethyl)(methyl)amino, (2,2,2-trifluoroethyl)(methyl)amino, diethylamino,
(3-hydroxyphenylmethyl)(methyl)amino, (3-methoxyphenylmethyl)(methyl)amino,
(2-hydroxyethyl)(methyl)amino, (2-hydroxyethyl)(ethyl)amino,
(2-methoxyethyl)(ethyl)amino, pyrrolidin-1 -yl, 3,3-difluoro-pyrrolidin-1-yl, 2-methyl- pyrrolidin-1 -yl, 2-trifluoromethyl-pyrrolidin-1 -yl, 3-hydroxy-pyrrolidin-1-yl, 2-hydroxymethyl- pyrrolidin-1-yl, 3-hydroxymethyl-pyrrolidin-1 -yl, 2,5-dimethyl-pyrrolidin-1 -yl, piperidin-1-yl, 4-fluoro-piperidin-1-yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, 3-methyl- piperidin-1-yl, 4-methyl-piperidin-1 -yl, 3-trifluoromethyl-piperidin-1 -yl, 4-trifluoromethyl- piperidin-1 -yl, 3,5-dimethyl-piperidin-1 -yl, 4,4-dimethyl-piperidin-1-yl, 4-cyano-piperidin-1- yl, 2-hydroxymethyl-piperidin-1 -yl, 3-hydroxymethyl-piperidin-1-yl, 4-hydroxymethyl- piperidin-1-yl, 2-methoxymethyl-piperidin-1-yl, 3-methoxymethyl-piperidin-1 -yl,
4-methoxymethyl-piperidin-1 -yl, 2-(2-hydroxyethyl)-piperidin-1-yl, 2-(2-methoxyethyl)- piperidin-1 -yl, 4-(2-hydroxyethyl)-piperidin-1-yl, 4-(2-methoxyethyl)-piperidin-1-yl,
3-hydroxy-piperidin-1 -yl, 4-hydroxy-piperidin-1-yl, 3-methoxy-piperidin-1-yl, 4-methoxy- piperidin-1 -yl, 4-dimethylamino-piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1 -yl, 4-methyl-piperazin-1 -yl, or 4-(2,2,2-trifluoroethyl)-piperazin-1 -yl.
Suitably, R3 is H.
In another embodiment of this invention, R2 and R3 taken together with atoms through which they are connected form a non-aromatic 5-membered ring, which may be unsubstituted or substituted with one or two substituents independently selected from (Ci-C4)alkyl, (Ci-C4)haloalkyl, hydroxy(Ci-C4)alkyl-, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, (Ci-C4)alkylthio-, (C C4)haloalkylthio-; -C02R , -(C C4)alkyl-C02R , -CORf , -CON(Rd)(Re), and -(C C4)alkyl-CON(Rd)(Re). In a specific embodiment of this invention, R2 and R3 taken together represent -CH2CH2-. Suitably, each R4 is independently selected from H, halogen, cyano, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C C4)haloalkyl, (C C4)alkoxy,
(d-C4)haloalkoxy, (C C4)alkylthio-, (C C4)haloalkylthio-, -C02R , -(C C4)alkyl-C02R , -CORf , -CON(Rd)(Re), -(Ci-C4)alkyl-CON(Rd)(Re), heterocycloalkyl, aryl, and heteroaryl; wherein the aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC4)alkyl, (C3-C6)cycloalkyl, (CrC4)haloalkyl, cyano, nitro, oxo,-ORc, -(Ci-C4)alkyl-ORc, -SRC, -(C C4)alkyl-SRc, -CO(Ci-C4)alkyl, -(Ci-C4)alkyl- CO(Ci-C4)alkyl, -CONHRd, -CON(Rd)(Re), -(C C4)alkyl-CON(Rd)(Re), -S02(C C4)alkyl, -(CrC4)alkyl-S02(Ci-C4)alkyl, -S02NHRd, -S02N(Rd)(Re), -(C C4)alkyl-S02N(Rd)(Re), -NHRd, -N(Rd)(Re), -(Ci-C4)alkyl-NHRd, -(C C4)alkyl-N(Rd)(Re), -C02Rf, -(C C4)alkyl- C02Rf, -NHS02(CrC4)alkyl, -(C C4)alkyl-NHS02(Ci-C4)alkyl, -NHCO(C C4)alkyl, -(CrC4)alkylNHCO(Ci-C4)alkyl, -NHCOO(C C4)alkylphenyl,
-(Ci-C4)alkylNHCOO(Ci-C4)alkylphenyl, aryl, or heteroaryl;
wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC6)alkyl, (C3-C6)cycloalkyl, (CrC4)haloalkyl, cyano, nitro, -ORc, -N(Rd)(Re), -CON(Rd)(Re), -C02Rc, -CO(C C4)alkyl, -S02N(Rd)(Re),
-S02(Ci-C4)alkyl,-NHCO(Ci-C4)alkyl, or -NHS02(Ci-C4)alkyl,
In another embodiment of this invention, each R4 is independently selected from H, F, CI, Br, (C C6)alkyl, (d-C4)haloalkyl, (C C4)alkoxy, (d-C4)haloalkoxy, (C C4)alkylthio-, cyano, -C02H, -C02(C C4)alkyl, -CONH2, -CONH(C C4)alkyl-,
-CONH((C1-C4)alkyl)((C1-C4)alkyl), -CO(pyrrolidin-l -yl), -CO(piperidin-l -yl), -CO(piperazin- 1-yl), -CO(morpholin-4-yl), -CO(thiomorpholin-4-yl), dihydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl; wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one to two times, independently, by halogen, (CrC4)alkyl, (Ci-C4)haloalkyl, cyano, -C02H, -C02(CrC4)alkyl, -CONH2, -CONH(Ci-C4)alkyl, -CONH((Ci-C4)alkyl)((C C4)alkyl), -S02NH2,
-S02NH(CrC4)alkyl, -S02NH((Ci-C4)alkyl)((C C4)alkyl), carboxy(C C4)alkyl-,
phenyl(Ci-C2)alkyloxycarbonylamino(Ci-C4)alkyl-, hydroxyl, (CrC4)alkoxy,
(Ci-C4)haloalkoxy, hydroxy(CrC4)alkyl-, (CrC4)alkoxy(Ci-C4)alkyl-, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, amino(Ci-C4)alkyl-,
(Ci-C4)alkylamino(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl-,
-NHCO(Ci-C4)alkyl, phenyl, halophenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl.
In a specific embodiment of this invention, at least one R4 is H, F, CI, Br, methyl, isopropyl, isobutyl, cyano, carboxy, isopropyloxycarbonyl, f-butyloxycarbonyl, pyrrolidin-1 - ylcarbonyl, furan-2-yl, furan-3-yl, 5-methyl-furan-2-yl, 1-methyl-pyrazol-4-yl, 1-methyl- pyrazol-5-yl, 3,6-dihydro-2H-pyran-4-yl, phenyl, 4-fluorophenyl, 2-chlorophenyl,
3- chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-f- butylphenyl, 3-trifluoromethylphenyl, 3,5-dimethylphenyl, 3-hydroxymethylphenyl,
4- hydroxymethylphenyl, 3-aminomethylphenyl, 4-aminomethylphenyl, 4-[(2- phenylmethoxycarbonylamino)ethyl]phenyl, 4-(carboxymethyl)phenyl, 4-(carboxy)phenyl,
3- (isopropoxycarbonyl)phenyl, 4-(aminocarbonyl)phenyl, 2-hydroxyphenyl,
4- hydroxyphenyl, 4-methoxyphenyl, 2-methoxy-5-isopropylphenyl, 3-aminophenyl, 4-dimethylaminophenyl, 4-acetylaminophenyl, 4-(aminosulfonyl)phenyl, 4'-chloro-4- biphenylyl, pyridin-3-yl, pyridin-4-yl, or 3-chloro-pyridin-4-yl.
Specific compounds of this invention include:
3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide,
3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide,
3-{[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/-methyl-4- (methyloxy)benzenesulfonamide,
3-{[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide,
4-(dimethylamino)-3-{[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
A/-methyl-4-(methyloxy)-3-{[5-(1-methyl-1 H-pyrazol-5-yl)-1 H-pyrrolo[2,3- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-(4-morpholinyl)-3-(1 /-/-pyrazolo[3,4-d]pyrimidin-4- ylamino)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide, /V-methyl-4-(4-morpholinyl)-3-[(3-phenyl-1 H-pyrazolo[3,4-d]pyrimidin-4- yl)amino]benzenesulfonamide,
3-{[3-(3-chlorophenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
/V-methyl-3-[(3-methyl-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(4- morpholinyl)benzenesulfonamide,
3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[ethyl(2- hydroxyethyl)amino]-/\/-methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-{ethyl[2- (methyloxy)ethyl]amino}-/\/-methylbenzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4- (methyloxy)benzenesulfonamide,
3-{[3-(2-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-
(methyloxy)benzenesulfonamide,
/V-methyl-3-{[3-(5-methyl-2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4- (methyloxy)benzenesulfonamide,
3- [(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide,
A/-methyl-4-(methyloxy)-3-{[3-(1-methyl-1 /-/-pyrazol-5-yl)-1 /-/-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
4- (dimethylamino)-3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
4-(dimethylamino)-/V-methyl-3-{[3-(5-methyl-2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin- 4-yl]amino}benzenesulfonamide,
4-(dimethylamino)-3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide ,
4-(dimethylamino)-/V-methyl-3-{[3-(1 -methyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
4-(dimethylamino)-/V-methyl-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-(methyloxy)-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-[(1 -methylethyl)oxy]-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide, /V-methyl-4-[(1 -methylethyl)oxy]-3-{[3-(1-methyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide,
/V-methyl-4-[(1 -methylethyl)oxy]-3-{[3-(5-methyl-2-furanyl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide
3-{[3-(3,6-dihydro-2H-pyran-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methyl-4-[(1 -methylethyl)oxy]benzenesulfonamide,
/V-methyl-4-[(1 -methylethyl)oxy]-3-[(3-methyl-1 /-/-pyrazolo[3,4-d]pyrimidin-4- yl)amino]benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(cyclohexyloxy)-/\/- methylbenzenesulfonamide,
3- [(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(1 - pyrrolidinyl)benzenesulfonamide,
4- fluoro-/V-methyl-3-(9/-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-(4-morpholinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-3-(1 /-/-purin-6-ylamino)-4-(1-pyrrolidinyl)benzenesulfonamide,
4-(dimethylamino)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, /V-methyl-4-(methyloxy)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-(1 -piperidinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-(4-methyl-1 -piperazinyl)-3-(1 H-purin-6-ylamino)benzenesulfonamide, /V-methyl-4-[(1 -methylethyl)oxy]-3-(1 H-purin-6-ylamino)benzenesulfonamide, /V-methyl-4-(1-piperazinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
4-{ethyl[2-(methyloxy)ethyl]amino}-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[ethyl(2-hydroxyethyl)amino]-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[(cyclohexylmethyl)oxy]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide,
4-(cyclopentyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
4-[(2-cyclohexylethyl)oxy]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide,
4-(cyclohexyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-3-(1 /-/-purin-6-ylamino)-4-{[2-(1 -pyrrolidinyl)ethyl]oxy}
benzenesulfonamide, 4-[3-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
/V-methyl-4-{[2-(1 -piperidinyl)ethyl]oxy}-3-(1 H-purin-6-ylamino)benzenesulfonamide 4-[4-(2-hydroxyethyl)-1 -piperidinyl]-/V-methyl-3-(1 H-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{[2-(4-piperidinyl)ethyl]oxy}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[ethyl(methyl)amino]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-[4-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[2-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-3-(1 H-purin-6-ylamino)-4-[4-(trifluoromethyl)-1 - piperidinyl]benzenesulfonamide,
A/-methyl-3-(1 H-purin-6-ylamino)-4-[3-(trifluoromethyl)-1 - piperidinyl]benzenesulfonamide,
4-[3-(hydroxymethyl)-1 -pyrrolidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[4-(dimethylamino)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-(3-hydroxy-1 -pyrrolidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-(4-cyano-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, /V-methyl-4-{2-[2-(methyloxy)ethyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[2-(2-hydroxyethyl)-1 -piperidinyl]-/V-methyl-3-(1 H-purin-6- ylamino)benzenesulfonamide,
4-(3-hydroxy-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-(4-hydroxy-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-[2-(hydroxymethyl)-1 -pyrrolidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-(cycloheptyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-[(1 -methylpropyl)oxy]-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-[(1 ,2-dimethylpropyl)oxy]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, /V-methyl-4-{[4-(methyloxy)cyclohexyl]oxy}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide, 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(2,2,2- trifluoroethyl)oxy]benzenesulfonamide,
/V-methyl-3-(1 H-purin-6-ylamino)-4-{[4- (trifluoromethyl)cyclohexyl]oxy}benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[(1 ,2-dimethylpropyl)oxy]-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4-methyl-1 - piperazinyl)benzenesulfonamide,
3-{[3-(3,6-dihydro-2H-pyran-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methyl-4-(methyloxy)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-/V-methyl-4-(1 - piperidinyl)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-[3-(hydroxymethyl)-1 - piperidinyl]-/V-methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-[4-(hydroxymethyl)-1 - piperidinyl]-/V-methylbenzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-(4-hydroxy-1-piperidinyl)-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-(3-hydroxy-1-piperidinyl)-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-/V-methyl-4-[(1- methylpropyl)oxy]benzenesulfonamide,
3- [(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-/V-methyl-4- (propyloxy)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-(butyloxy)-/V- methylbenzenesulfonamide,
4- (4-fluoro-1-piperidinyl)-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide, A/-methyl-4-{3-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{2-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 H-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{4-[2-(methyloxy)ethyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-[3-(methyloxy)-1 -piperidinyl]-3-(1 H-purin-6- ylamino)benzenesulfonamide, A/-methyl-4-[4-(methyloxy)-1 -piperidinyl]-3-(1 H-purin-6- ylamino)benzenesulfonamide,
/V-methyl-4-{4-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-(4-methyl-1 -piperidinyl)-3-(1 H-purin-6-ylamino)benzenesulfonamide,
/V-methyl-3-(1 /-/-purin-6-ylamino)-4-[(2,2,2-trifluoroethyl)oxy] benzenesulfonamide, 4-(3,5-dimethyl-1-piperidinyl)-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-3-(1 /-/-purin-6-ylamino)-4-[(3,3,3-trifluoropropyl)oxy]benzenesulfonamide, A/-methyl-3-(1 H-purin-6-ylamino)-4-[2-(trifluoromethyl)-1 -pyrrolidinyl]
benzenesulfonamide,
/V-methyl-3-(1 H-purin-6-ylamino)-4-[(3,3,3-trifluoro-1- methylpropyl)oxy]benzenesulfonamide,
4-(dimethylamino)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide,
A/-ethyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide,
4-fluoro-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide, A/-methyl-4-(4-morpholinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-5-(1 /-/-pyrrolo[2,3-d]pyrimidin-4-ylamino)-3-pyridinesulfonamide,
4-[ethyl(methyl)amino]-/\/-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(diethylamino)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-[(2-hydroxyethyl)(methyl) amino]-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-[4-(2,2,2-trifluoroethyl)-1- piperazinyl]benzenesulfonamide,
A/-methyl-4-(methyloxy)-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-4-[(1 -methylethyl)oxy]-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-4-(methylthio)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-1 -(1 H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1 H-indole-6-sulfonamide, /V-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfona
3-[(5-fluoro-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide,
3-[(5-chloro-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide,
/V,4-dimethyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide, 3-[(5-chloro-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
3-[(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide,
3-[(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
3-[(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
3-[(5-chloro-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
1-(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)-/\/-methyl-2,3-dihydro-1 /-/-indole-6- sulfonamide,
3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methylthio)benzenesulfonamide,
A/-methyl-3-({5-[4-(methyloxy)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl}amino)benzenesulfonamide,
A/-methyl-3-[(5-phenyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfonamide,
A/-methyl-3-{[5-(3-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[5-(4-chlorophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
A/-methyl-3-{[5-(4-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[5-(2-chlorophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3-{[5-(3-chlorophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
A/-methyl-3-{[5-(2-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-({5-[4-(dimethylamino)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3-({5-[4-(aminomethyl)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide, /V-methyl-3-({5-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4- yl}amino)benzenesulfonamide,
/V-methyl-3-{[5-(4-pyridinyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
A/-methyl-3-{[5-(3-pyridinyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
4-[4-({3-[(methylamino) sulfonyl]phenyl}amino)-1 H-pyrrolo[2,3-d]pyrimidin-5- yl]benzamide,
3-{[5-(3-aminophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3-{[5-(3-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3- {[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-{4-[4-({3-[(methylamino)sulfonyl]phenyl} amino)-1 H-pyrrolo[2,3-d]pyrimidin-5- yl]phenyl}acetamide,
4- [4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 /-/-pyrrolo[2,3-d]pyrimidin-5- yl]benzoic acid,
3-({5-[3-(aminomethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3-{[5-(4-fluorophenyl)-1 H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
{4-[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3-d]pyrimidin-5- yl]phenyl}acetic acid,
3-({5-[4-(aminosulfonyl)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
phenylmethyl (2-{4-[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3- d]pyrimidin-5-yl]phenyl}ethyl)carbamate,
3-{[5-(4'-chloro-4-biphenylyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3-[(5-cyano-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methylbenzenesulfonamide, A/-methyl-3-{[5-(1 -methylethyl)-1 H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
A/-methyl-4-(1 -pyrrolidinyl)-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide, A/-methyl-4-(1 -piperidinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-(2-methyl-1 -pyrrolidinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(2,5-dimethyl-1-pyrrolidinyl)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(3,5-dimethyl-1-piperidinyl)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-(4-methyl-1 -piperidinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-(3-methyl-1 -piperidinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-[(2R)-2-methyl-1 -pyrrolidinyl]-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-(4- thiomorpholinyl)benzenesulfonamide,
/V-methyl-4-[(2S)-2-methyl-1-pyrrolidinyl]-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(4,4-dimethyl-1-piperidinyl)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-[(3R,5S)-3,5-dimethyl-1-piperidinyl]-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
3-[(6-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide,
3- [(5,6-dibromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide,
4- ({3-[(methylamino) sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3-d]pyrimidine-6- carboxylic acid,
1 , 1 -dimethylethyl 4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 /-/-pyrrolo[2,3- d]pyrimidine-6-carboxylate,
1-methylethyl 4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 /-/-pyrrolo[2,3- d]pyrimidine-6-carboxylate,
3-[(6-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
3-[(6-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide, /V-methyl-3-{[6-(1 -pyrrolidinylcarbonyl)-1 H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
/V-methyl-3-[(6-phenyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfonamide,
/V-methyl-3-{[6-(2-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[6-(2-hydroxyphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-methyl-3-({6-[3-(trifluoromethyl)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl}amino)benzenesulfonamide,
3-({6-[3-(hydroxymethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3-({6-[4-(1 -dimethylethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3-{[6-(4-hydroxyphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-methyl-3-{[6-(4-pyridinyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
/V-methyl-3-{[6-(4-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
/V-methyl-3-{[6-(3-methylphenyl)-1 H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[6-(3,5-dimethylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3-{[6-(3-chloro-4-pyridinyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
A/-methyl-3-({6-[5-(1 -methylethyl)-2-(methyloxy)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin- 4-yl}amino)benzenesulfonamide,
3-({6-[4-(hydroxymethyl)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
1 , 1 -dimethylethyl 3-[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3- d]pyrimidin-6-yl]benzoate,
/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide,
A/-4-dimethyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
A/-methyl-3-(1 /-/-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzenesulfonamide,
4-(dimethylamino)-/V-methyl-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide, A/-methyl-1 -(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1 H-indole-6- sulfonamide,
4-(dimethylamino)-/V-methyl-3-({6-[3-(trifluoromethyl)phenyl]-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl}amino)benzenesulfonamide,
/V-methyl-4-(4-morpholinyl)-3-({6-[3-(trifluoromethyl)phenyl]-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl}amino)benzenesulfonamide,
/V-methyl-4-(methyloxy)-3-({6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin- 4-yl}amino)benzenesulfonamide,
/V-methyl-1-{6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}-2,3- dihydro-1 H-indole-6-sulfonamide,
/V-methyl-4-(methyloxy)-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
/V-methyl-4-(methyloxy)-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
A/-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(4- morpholinyl)benzenesulfonamide,
/V-methyl-4-(methylthio)-3-({6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3- d]pyrimidin-4-yl}amino)benzenesulfonamide,
4-(dimethylamino)-/\/-methyl-3-{[6-(1 -pyrrolidinylcarbonyl)-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-(4-morpholinyl)-3-{[6-(1-pyrrolidinylcarbonyl)-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl]amino}benzenesulfonamide,
/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-[(2,2,2- trifluoroethyl)oxy]benzenesulfonamide,
4-(ethyloxy)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-hydroxy-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide, /V-methyl-4-(propylamino)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-2-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-biphenylsulfonamide,
/V-methyl-2-({6-[3-(trifluoromethyl)phenylH
biphenylsulfonamide,
A/-methyl-4-(1 -methyl-1 H-pyrazol-5-yl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-4-(1 -methyl-1 H-pyrazol-5-yl)-3-({6-[3-(trifluoromethyl)phenyl]-1 H- pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzenesulfonamide, /V-methyl-3-{[5-(2-methylpropyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/V-methyl-4-(4-methyl-1- piperidinyl)benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-{4- [(methyloxy)methyl]-1-piperidinyl}benzenesulfonamide,
3-{[3-(3-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(4-hydroxy-1 - piperidinyl)-/V-methylbenzenesulfonamide,
3-{[3-(3-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(3-hydroxy-1 - piperidinyl)-/V-methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[4- (trifluoromethyl)-1-piperidinyl]benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-{4- [(methyloxy)methyl]-1-piperidinyl}benzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[4-(methyloxy)-1 - piperidinyl]benzenesulfonamide,
3- [(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4-methyl-1 - piperidinyl)benzenesulfonamide,
/V-methyl-4-({[3-(methyloxy)phenyl]methyl}amino)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
/V-methyl-4-({[3-(methyloxy)phenyl]methyl}oxy)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
/V-methyl-4-(methyl{[3-(methyloxy)phenyl]methyl}amino)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-(2-methyl-1 -pyrrolidinyl)-3-(1 H-purin-6-ylamino)benzenesulfonamide
4- [[(3-hydroxyphenyl)methyl](methyl)amino]-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
3-{[3-(3-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(3-hydroxy-1 - piperidinyl)-/V-methylbenzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(2-methyl-1 - pyrrolidinyl)benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/V-methyl-4-(2-methyl-1- pyrrolidinyl)benzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[ethyl(methyl)amino]-/\/- methylbenzenesulfonamide, /V-methyl-4-[(2S)-2-methyl-1-pyrrolidinyl]-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyn yl)amino]benzenesulfonamide,
4-(4,4-difluoro-1 -piperidinyl)-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methy-3-{1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-[(2R)-2-trifluorom
pyrrolidinyl]benzenesulfonamide,
/V-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-[(2R)-2- (trifluoromethyl)-1-pyrrolidinyl]benzenesulfonamide,
3- [(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methyl-4-[(2S)-2-meth pyrrolidinyl]benzenesulfonamide,
/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4- [(trifluoromethyl)oxy]benzenesulfonamide,
4- fluoro-/V-methyl-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
4-(2,5-dimethyl-1-pyrrolidinyl)-/V-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimi yl)amino]benzenesulfonamide,
4-chloro-/V-methyl-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
4-chloro-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylam
/V-methyl-4-[methyl(2,2,2-trifluoroethyl)amino]-3-(1 H-pyrrolo[2,3-d]pyrimi ylamino)benzenesulfonamide,
4-(3,3-difluoro-1 -pyrrolidinyl)-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(3,3-difluoro-1 -piperidinyl)-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
and a salt, particularly a pharmaceutically acceptable salt, thereof.
Representative compounds of this invention include the compounds of Examples
1-241.
The compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit
polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
For solvates of the compounds of the invention, or salts thereof, that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
Because of their potential use in medicine, the salts of the compounds of Formula I are preferably pharmaceutically acceptable. The compounds of this invention are bases, wherein a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates and naphthalene-2-sulfonates.
Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a
pharmaceutically acceptable salt may be made with a base which affords a
pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, Λ/,Λ/'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
dehydroabietylamine, /V,/V'-i)/sdehydroabietylamine, glucamine, /V-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine. If an inventive basic compound is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound. Similarly, if a disclosed compound containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pKa than the free acid form of the compound.
General Methods of Preparation
The compounds of Formula I may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist. The synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different R1, R2, and R3 groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula I, they are illustrative of processes that may be used to make the compounds of the invention.
Compound names were generated using the software naming program ACD/Name Pro V6.02 available from Advanced Chemistry Development, Inc., 1 10 Yonge Street, 14th Floor, Toronto, Ontario, Canada, M5C 1T4 (http://www.acdlabs.com/).
As shown in Schemes 1 , 7, 9 and 10, the compounds of Formula I can be prepared under a variety of conditions by reaction of an aryl/heteroaryl amine (e.g., Ar- NH-R3) with an activated pyrrolopyrimidine.
Scheme 1
Figure imgf000031_0001
a) Ar-NH-R3, AgOTf, DMF, 80-100 °C, 5-20 h; b) Ar-NH-R3, isopropanol, μw, 100-150 °C, 10-25 min; c) Ar-NH-R3, AgOTf, isopropanol, μw, 100- 160 °C, 0.5-1 .25 h; d) Ar-NH-R3, AgOTf, isopropanol, μw, 80 °C, 16-42 h; e) Ar-NH-R3, isopropanol, aq. HCI, μνν, 150 °C, 30-60 min; f) ArNH-R3, 1 ,4- dioxane, AcOH, 90 °C, 24 h
As shown in Schemes 2-5, introduction of substituents on the pyrrolopyrimidine or pyrazolopyrimidine moiety may be accomplished by organometallic (palladium-mediated) coupling reactions.
Scheme 2
Figure imgf000032_0001
a) R4-B(OR)2, Pd(dppf)CI2, Na2C03, 1 ,4-dioxane, 100 °C, overnight; b) R4- B(OR)2, Pd(PPh3)4, Na2C03, 1 ,4-dioxane, 100 °C, overnight; c) R4-B(OR)2, Pd(f-Bu3P)2 K2C03, 1 ,4-dioxane, water, μw, 150 °C, 40 min; d) CuCN, DMF, μw, 210 °C, 60 min
Scheme 3
Figure imgf000032_0002
a) Boc20, DMAP, CH3CN, 25 °C, 1 h; b) R4-B(OR)2, Pd(dppf)CI2, Na2C03, 1 ,4-dioxane, 100 °C, 16 h
Scheme 4
Figure imgf000032_0003
a) R4-B(OR)2, PdCI2(dppf), Na2C03, 1 ,4-dioxane/H20, μνν, 120 °C, 15 min; b) R4-B(OR)2, Pd(PhP3)4, Na2C03, μνν, 1 ,4-dioxane/H20, 120-160 °C, 15 min Schem
Figure imgf000033_0001
a) Boc20, DMAP, CH3CN, 25 °C, 15 min; b) isopropenylboronic acid pinacol ester, Pd(dppf)CI2, Na2C03, 1 ,4-dioxane, 100 °C, 16 h; c) H2 (1 atm.), Pd/C, MeOH, 25 °C, 16 h; d) HCI in 1 ,4-dioxane, CH3CN, 25 °C, 16 h
As shown in Schemes 6, 7, 9, 10 and 1 1 introduction of substituents at various positions of the aryl/heteroaryl-amino-pyrrolopyrimidine moiety may be accomplished by routine transformations.
Figure imgf000033_0002
a) NH(Ra)(Rb), 80 °C, 16 h; b) NH(Ra)(Rb), DMSO, μνν, 150 °C, 30 min
Figure imgf000033_0003
a) Ar-NH-R3, AgOTf, isopropanol, μνν, 120 °C, 30 min; b) NH(Rd)(Re), PyBOP, /'-Pr2NEt, DMF, rt, overnight
As shown in Scheme 8, the compounds of Formula I can be prepared under a variety of conditions by reaction of an aryl/heteroaryl amine (e.g., Ar-NH-R3) with an activated pyrrolopyrimidine, pyrazolopyrimidine, or imidazopyrimidine.
Scheme 8
Figure imgf000034_0001
a) Ar-NH-R3, isopropanol, 80 °C, 16-42 h; b) Ar-NH-R3, DMF, AgOTf, 80 °C, 16-20 h; c) Ar-NH-R3, 1 ,4-dioxane, AgOTf, 80-100 °C, 16-72 h; d) Ar-NH-R3, 1 ,4-dioxane, DIPEA, 80-100 °C, 16-72 h; e) Ar-NH-R3, 1 ,4- dioxane, AcOH, 80-100 °C, 20-72 h
Scheme 9
Figure imgf000034_0002
a) AgOTf, NMP, 160 °C, 60 h; b) R2-B(OH)2, Pd(dppf)CI2, K2C03, 1 ,4- dioxane, water, 140 °C, 4 h Scheme 10
Figure imgf000035_0001
a) AgOTf, DMF, 140 °C, 4 h; b) H2, Pd/C, MeOH, 30 psi, 25 °C, 16 h
Scheme 11
Figure imgf000035_0002
a) RcOH, NaH, NMP, 1 10 °C, 20-120 h; b) RcOH, NaH, 1 10 °C, 20 h; c) RcOH, NaH, 1 ,4-dioxane, 24 °C, 1 h
The invention also includes various deuterated forms of the compounds of Formula
I. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula I. For example, deuterated alkyl groups (/V-(deuteromethyl) amines or Ra/Rb or Rd/Re alkyls) may be prepared by conventional techniques (see for example: methyl-c/3-amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2). Employing such compounds according to Scheme 1 or Scheme 2 will allow for the compounds of Formula I in which various hydrogen atoms of the /V-methyl, phenyl or pyrimidinyl groups are replaced with a deuterium atom. Methods of Use
The present invention is directed to a method of inhibiting TNNI3K which comprises contacting the kinase with a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof. This invention is also directed to a method of treatment of a TNNI3K-mediated disease or disorder comprising administering an effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof. As used herein, "patient" refers to a human or other mammal. Specifically, this invention is directed to a method of inhibiting TNNI3K activity, comprising contacting the kinase with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. For example, TNNI3K activity may be inhibited in mammalian cardiac tissue by administering to a patient in need thereof, an effective amount a compound of Formula I or a pharmaceutically acceptable salt thereof.
The compounds of this invention may be particularly useful for treatment of TNNI3K-mediated diseases or disorders, specifically by inhibition of TNNI3K activity, where such diseases or disorders are selected from heart failure, particularly congestive heart failure; cardiac hypertrophy; and heart failure or congestive heart failure resulting from cardiac hypertrophy. The compounds of this invention may also be useful for the treatment of heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.
A therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to modulate or inhibit the activity of TNNI3K such that a disease condition which is mediated by that activity is reduced, allew'ated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC5o), efficacy (EC5o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
"Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by TNNI3K. The methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease. The compounds of Formula I of this invention may be useful for the treatment of heart failure, particularly congestive heart failure. The compounds of Formula I of this invention may be useful for the treatment of cardiac hypertrophy, and heart failure or congestive heart failure resulting from cardiac hypertrophy, myocardial ischemia or myocardial infarction.
The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin.
The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Treatment of TNNI3K-mediated disease conditions may be achieved using the compounds of this invention as a monotherapy, or in dual or multiple combination therapy, such as in combination with other cardiovascular agents, for example, in combination with one or more of the following agents: a beta-blocker, an ACE inhibitor, an angiotensin receptor blocker (ARB), a calcium channel blocker, a diuretic, a renin inhibitor, a centrally acting antihypertensive, a dual ACE/NEP inhibitor, an aldosterone synthase inhibitor, and an aldosterone-receptor antagonist, which are administered in effective amounts as is known in the art.
Examples of suitable beta blockers include timolol (such as Blocarden™), carteolol (such as Cartrol™), carvedilol (such as Coreg™), nadolol (such as Corgard™), propanolol (such as Innopran XL™), betaxolol (such as Kerlone™), penbutolol (such as Levatol™), metoprolol (such as LopressortM and Toprol-XL™), atenolol (such as Tenormin™), pindolol (such as Visken™), bisoprolol, bucindolol, esmolol, acebutolol, labetalol, nebivolol, celiprolol, sotalol, and oxprenolol. Examples of suitable ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril. Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril. Examples of suitable angiotensin receptor blockers include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan. Examples of suitable calcium channel blockers include dihydropyridines (DHPs) and non-DHPs. Suitable DHPs include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine,
nimodiphine, nisoldipine, nitrendipine, and nivaldipine, and their pharmaceutically acceptable salts. Suitable non-DHPs are flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verampimil, and their pharmaceutically acceptable salts. A suitable diuretic is a thiazide derivative selected from amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon. A suitable renin inhibitor is aliskiren. Examples of suitable centrally acting antiphypertensives include clonidine, guanabenz, guanfacine and methyldopa. Examples of suitable dual ACE/NEP inhibitors include omapatrilat, fasidotril, and fasidotrilat. Examples of suitable aldosterone synthase inhibitors include anastrozole, fadrozole, and exemestane. Examples of suitable aldosterone-receptor antagonists include spironolactone and eplerenone.
A compound of the invention may be employed alone, in combination with one or more other compounds of the invention or in combination with other therapeutic methods or agents. In particular, in methods of treating a condition attenuated by inhibition of at least one Raf family kinase and in methods of treating susceptible neoplasms, combination with other chemotherapeutic, biologic, hormonal, antibody and supportive care agents is envisaged as well as combination with surgical therapy and radiotherapy. Supportive care agents include analgesics, anti-emetics and agents used to treat heamatologic side effects such as neutropenia. Analgesics are well known in the art. Anti-emetics include but are not limited to 5HT3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like; prochlorperazine; metaclopromide; diphenhydramine; promethazine; dexamethasone; lorazepam; haloperidol; dronabinol; olanzapine; and neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopitant administered alone or in various combinations.
The term "chemotherapeutic" as used herein refers to any chemical agent having a therapeutic effect on the subject to which it is administered. "Chemotherapeutic" agents include but are not limited to anti-neoplastic agents. As used herein, "anti-neoplastic agents" include both cytotoxic and cytostatic agents including biological, immunological and vaccine therapies. Combination therapies according to the invention thus comprise the administration of at least one compound of the invention and the use of at least one other treatment method. In one embodiment, combination therapies according to the invention comprise the administration of at least one compound of the invention and surgical therapy. In one embodiment, combination therapies according to the invention comprise the administration of at least one compound of the invention and radiotherapy. In one embodiment, combination therapies according to the invention comprise the administration of at least one compound of the invention and at least one supportive care agent (e.g., at least one anti-emetic agent). In one embodiment, combination therapies according to the present invention comprise the administration of at least one compound of the invention and at least one other chemotherapeutic agent. In one particular embodiment, the invention comprises the administration of at least one compound of the invention and at least one anti-neoplastic agent.
As an additional aspect, the present invention provides the methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one chemotherapeutic agent. In one particular embodiment, the chemotherapeutic agent is an anti-neoplastic agent. In another embodiment, the invention provides a pharmaceutical composition as described above further comprising at least one other chemotherapeutic agent, more particularly, the chemotherapeutic agent is an antineoplastic agent. The invention also provides methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one supportive care agent (e.g., anti-emetic agent). The compounds of the invention and at least one additional anti-neoplastic or supportive care therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination. The administration of a compound of the invention with one or more other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in one unitary
pharmaceutical composition including both or all compounds or two or more separate pharmaceutical compositions each including one or more of the compounds. The components of the combination may be administered separately in a sequential manner wherein one active ingredient is administered first and the other(s) second or vice versa. Such sequential administration may be close in time or remote in time.
When a compound of the invention is used in combination with an anti-neoplastic and/or supportive care agent, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. The appropriate dose of the compound(s) of the invention and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.
Typically, any chemotherapeutic agent that has activity against a susceptible neoplasm being treated may be utilized in combination with the compounds of the invention, provided that the particular agent is clinically compatible with therapy employing a compound of the invention. Typical anti-neoplastic agents useful in the present invention include, but are not limited to: alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents, topoisomerase I and II inhibitors, hormones and hormonal analogues; retinoids, signal transduction pathway inhibitors including inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or other kinase inhibitors; cyclin dependent kinase inhibitors; antisense therapies and
immunotherapeutic agents, including monoclonals, vaccines or other biological agents.
Alkylating agents are non-phase specific anti-neoplastic agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death. Alkylating agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of alkylating agents include but are not limited to nitrogen mustards such as cyclophosphamides, temozolamide, melphalan, and chlorambucil; oxazaphosphor-ines; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; triazenes such as dacarbazine; and platinum
coordination complexes such as cisplatin, oxaliplatin and carboplatin.
Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. The end result of discontinuing S phase is cell death. Antimetabolite neoplastic agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antimetabolite anti-neoplastic agents include but are not limited to purine and pyrimidine analogues and anti-folate compounds, and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mecaptopurine and thioguanine.
Antitumor antibiotic agents are non-phase specific agents, which bind to or intercalate with DNA. Typically, such action disrupts ordinary function of the nucleic acids, leading to cell death. Antitumor antibiotics may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antitumor antibiotic agents include, but are not limited to, actinomycins such as dactinomycin; anthracyclines such as daunorubicin, doxorubicin, idarubicin, epirubicin and mitoxantrone; mitomycin C and bleomycins.
Antimicrotubule or antimitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Antimitotic agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antimitotic agents include, but are not limited to, diterpenoids, vinca alkaloids, polo-like kinase (PIk) inhibitors and CenpE inhibitors. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vindesine and vinorelbine. PIk inhibitors are discussed further below.
Topoisomerase inhibitors include inhibitors of Topoisomerase II and inhibitors of Topoisomerase I. Topoisomerase II inhibitors, such as epipodophyllotoxins, are antineoplastic agents derived from the mandrake plant, that typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, causing DNA strand breaks. The strand breaks accumulate and cell death follows.
Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Camptothecins, including camptothecin and camptothecin derivatives, are available or under development as Topoisomerase I inhibitors. Examples of camptothecins include, but are not limited to amsacrine, irinotecan, topotecan, and the various optical forms of 7- (4-methylpiperazino-methylene)-10, 1 1-ethylenedioxy-20-camptothecin. Topoisomerase inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Antitumor hormones and hormonal analogues may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to antiestrogens, such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene and droloxifene; anti-androgens; such as flutamide, nilutamide, bicalutamide and cyproterone acetate;
adrenocorticosteroids such as prednisone and prednisolone; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane;
progestrins such as megestrol acetate; 5a-reductase inhibitors such as finasteride and dutasteride; and gonadotropin-releasing hormones (GnRH) and analogues thereof, such as Leutinizing Hormone-releasing Hormone (LHRH) agonists and antagonists such as goserelin luprolide, leuprorelin and buserelin.
Retinoid(s) are compounds that bind to and activate at least one retinoic acid receptor selected from RARa, RAR3, and RARy and/or compounds that bind to and activate at least one of RARa, RAR3, and RARy and also at least one retinoic X receptor (RXR), including RXRa, RXR3, and RXRy. Retinoids for use in the present invention typically have affinity for RAR, and particularly for RARa and/or RAR3. However, certain synthetic retinoids, such as 9-cis-retinoic acid also have affinity for both RAR and RXR. In one embodiment, the retinoid has affinity for RARa (and RARa agonist).
Examples of specific retinoids that may be used in combination with the compounds of the invention include: retinoic acid; all-trans-retinoic acid ("ATRA" also known as "tretinoin"); tamibarotene ("Am80"); 9-cis-retinoic acid ((2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6- trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic Acid) (also known as "9-cis-Tretinoin") (available from Sigma); Isotretinoin ((2Z,4£,6£,8£)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid) (also known as "13-cis-retinoic acid")
(Accutane®); Am580 (4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtamido) benzoic acid), See, M. Gianni, Blood (1996) 87 1520-1531 ; TTNPB (4-[E-2-(5,6,7,8-Tetrahydro- 5,5,8,8-tetramethyl-2-naphthalenyl)-1 -propenyl]benzoic acid) (also known as "Ro 13- 7410") See, M.F. Boehm et al., J. Med. Chem. (1994) 37 2930 and R.P. Bissonnette et al., Mol. Cell. Biol. (1995) 15 5576; and BMS753 (4-[[(2,3-dihydro-1 , 1 ,3,3-tetramethyl-2-oxo- 1 H-inden-5-yl)carbonyl]amino]benzoic acid) See, USPN 6184256.
Other RARa agonists known the art may also be used in the present invention. Signal transduction pathway inhibitors are those inhibitors which block or inhibit a chemical process which evokes an intracellular change. As used herein these changes include, but are not limited to, cell proliferation or differentiation or survival. Signal transduction pathway inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases, myoinositol signaling, and Ras oncogenes. Signal transduction pathway inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases. Receptor tyrosine kinase inhibitors which may be combined with the compounds of the invention include those involved in the regulation of cell growth, which receptor tyrosine kinases are sometimes referred to as "growth factor receptors." Examples of growth factor receptor inhibitors, include but are not limited to inhibitors of: insulin growth factor receptors (IGF- 1 R, IR and IRR); epidermal growth factor family receptors (EGFR, ErbB2, and ErbB4); platelet derived growth factor receptors (PDGFRs), vascular endothelial growth factor receptors (VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), macrophage colony stimulating factor (c-fms), c-kit, c- met, fibroblast growth factor receptors (FGFRs), hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB, and TrkC), ephrin (Eph) receptors and the RET protooncogene.
Several inhibitors of growth factor receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors, anti-sense oligonucleotides and aptamers. Any of these growth factor receptor inhibitors may be employed in combination with the compounds of the invention in any of the compositions and methods/uses described herein. Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibody inhibitor of growth factor function. One example of an anti-erbB1 antibody inhibitor of growth factor function is cetuximab (Erbitux™, C225). Bevacizumab (Avastin®) is an example of a monoclonal antibody directed against VEGFR. Examples of small molecule inhibitors of epidermal growth factor receptors include but are not limited to lapatinib (Tykerb®) and erlotinib (Tarceva®). Imatinib (Gleevec®) is one example of a PDGFR inhibitor. Examples of VEGFR inhibitors include pazopanib (Votrient™), ZD6474, AZD2171 , PTK787, sunitinib and sorafenib. In one embodiment, the invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with an EGFR or ErbB inhibitor. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with lapatinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with trastuzumab. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with erlotinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with gefitinib.
In another embodiment, the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a VEGFR inhibitor. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with pazopanib.
Tyrosine kinases that are not transmembrane growth factor receptor kinases are termed non-receptor, or intracellular tyrosine kinases. Inhibitors of non-receptor tyrosine kinases are sometimes referred to as "anti-metastatic agents" and are useful in the present invention. Targets or potential targets of anti-metastatic agents, include, but are not limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl and Bcr-Abl), FAK (focal adhesion kinase) and Bruton's tyrosine kinase (BTK). Non-receptor kinases and agents, which inhibit non-receptor tyrosine kinase function, are described in Sinha, S. and Corey, S.J., J. Hematother. Stem Cell Res. (1999) 8 465-80; and Bolen, J.B. and Brugge, J.S., Annu. Rev. of Immunol. (1997) 15 371-404.
SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, but not limited to, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. Examples of Src inhibitors include, but are not limited to, dasatinib and BMS-354825 (J. Med. Chem. (2004) 47 6658-6661 ).
Inhibitors of serine/threonine kinases may also be used in combination with the compounds of the invention in any of the compositions and methods described above. Examples of serine/threonine kinase inhibitors that may also be used in combination with a compound of the present invention include, but are not limited to, polo-like kinase inhibitors (Plk family e.g., Plk1 , Plk2, and Plk3), which play critical roles in regulating processes in the cell cycle including the entry into and the exit from mitosis; MAP kinase cascade blockers, which include other Ras/Raf kinase inhibitors, mitogen or extracellular regulated kinases (MEKs), and extracellular regulated kinases (ERKs); Aurora kinase inhibitors (including inhibitors of Aurora A and Aurora B); protein kinase C (PKC) family member blockers, including inhibitors of PKC subtypes (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta); inhibitors of kappa-B (IkB) kinase family (IKK-alpha, IKK-beta);
PKB/Akt kinase family inhibitors; and inhibitors of TGF-beta receptor kinases. Examples of PIk inhibitors are described in PCT Publication No. WO04/014899 and WO07/03036. Other examples of serine/threonine kinase inhibitors are known in the art. In another embodiment, the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a PIk inhibitor. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with 5-{6- [(4-methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1 -yl}-3-{(1 R)-1-[2- (trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.
Urokinase, also referred to as urokinase-type Plasminogen Activator (uPA), is a serine protease. Activation of the serine protease plasmin triggers a proteolysis cascade which is involved in thrombolysis or extracellular matrix degradation. Elevated expression of urokinase and several other components of the plasminogen activation system have been correlated with tumor malignancy including several aspects of cancer biology such as cell adhesion, migration and cellular mitotic pathways as well. Inhibitors of urokinase expression may be used in combination with the compounds of the invention in the compositions and methods described above.
Inhibitors of Ras oncogene may also be useful in combination with the compounds of the present invention. Such inhibitors include, but are not limited to, inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti- sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block Ras activation in cells containing mutant Ras, thereby acting as antiproliferative agents.
Inhibitors of kinases involved in the IGF-1 R signaling axis may also be useful in combination with the compounds of the present invention. Such inhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K, AKT and MEK, and 14.3.3 signaling inhibitors. Examples of AKT inhibitors are described in PCT Publication No. WO 2007/058850, published 24 May 2007 which corresponds to PCT Application No. PCT/US2006/043513, filed 9 Nov 2006. One particular AKT inhibitor disclosed therein is 4-(2-(4-amino-1 ,2,5- oxadiazol-3-yl)-1 -ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1 /-/-imidazo[4,5-c]pyridin-4-yl)-2- methyl-3-butyn-2-ol. Cell cycle signaling inhibitors, including inhibitors of cyclin dependent kinases (CDKs) are also useful in combination with the compounds of the invention in the compositions and methods described above. Examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania G. R. et al., Exp. Opin. Ther. Patents (2000) 10 215-230.
Receptor kinase angiogenesis inhibitors may also find use in the present invention. Inhibitors of angiogenesis related to VEGFR and TIE-2 are discussed above in regard to signal transduction inhibitors (both are receptor tyrosine kinases). Other inhibitors may be used in combination with the compounds of the invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav beta3) that inhibit angiogenesis; endostatin and angiostatin (non-rtK) may also prove useful in combination with the compounds of the invention. One example of a VEGFR antibody is bevacizumab (Avastin®).
Inhibitors of phosphatidyl inositol-3-OH kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in combination with the present invention.
Also of potential use in combination with the compounds of the invention are myoinositol signaling inhibitors such as phospholipase C blockers and myoinositol analogues. siRNA, RNAi, locked nucleic acid polynucleotides, and antisense therapies may also be used in combination with the compounds of the invention. Examples of such antisense therapies include those directed towards the targets described above such as ISIS 2503 and gene therapy approaches such as those using thymidine kinase or cytosine deaminase.Agents used in immunotherapeutic regimens may also be useful in
combination with the compounds of the invention. Immunotherapeutic regimens include ex-vivo and in-vivo approaches to increasing immunogenicity of patient tumor cells such as transfection with cytokines (eg. IL-2, IL-4, GMCFS and MCFS), approaches to increase T-cell activity, approaches with transfected immune cells and approaches with anti- idiotypic antibodies. Another potentially useful immunotherapeutic regimen is monoclonal antibodies with wild-type Fc receptors that may illicit an immune response in the host (e.g., IGF-1 R monoclonal antibodies).
Agents used in proapoptotic regimens (e.g., Bcl-2 antisense oligonucleotides) may also be used in combination with the compounds of the invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of Bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the Bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of Bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for Bcl-2 are discussed in Water, J.S. et al., J. Clin. Oncol. (2000) 18 1812-1823; and Kitada, S. et al., Antisense Res. Dev. (1994) 4 71-79.
The invention further includes the use of compounds of the invention as an active therapeutic substance, in particular in the treatment of diseases mediated by TNNI3K or B-Raf kinase. Specifically, the invention includes the use of compounds of the invention in the treatment of heart failure, particularly congestive heart failure; cardiac hypertrophy; heart failure or congestive heart failure resulting from cardiac hypertrophy; and heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction. Additionally, the invention includes the use of compounds of the invention in the treatment of susceptible neoplasms. Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer;
cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and
erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
In another aspect, the invention includes the use of compounds of the invention in the manufacture of a medicament for use in the treatment of the above disease and disorders. Compositions
The compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
As used herein, "pharmaceutically-acceptable excipient" means a material, composition or vehicle involved in giving form or consistency to the composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically-acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
The compounds of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing
Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
EXAMPLES
The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
the following experimental descriptions, the following abbreviations may be
Figure imgf000051_0001
min minute(s)
MS mass spectrum
Na2C03 sodium carbonate
NaH sodium hydride
NaHCOs sodium bicarbonate
Na2S04 sodium sulfate
n-BuLi n-butyllithium
NH4CI ammonium chloride
NH4OH ammonium hydroxide
NMP N-methyl-2-pyrrolidone
Pd/C palladium on carbon
Pd(dppf)CI2 [1, 1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(ll)
Pd(Ph3)4 tetrakis(triphenylphosphine)palladium(0)
Pd(t-Bu3P)2 bis(tri-t-butylphosphine)palladium(0)
POCh phosphoryl chloride
PyBOP benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate rt room temperature
sat. saturated
sex strong cation exchange
TFA trifluoroacetic acid
THF tetrahydrofuran
tR retention time
PREPARATION 1
4-fluoro-/V-methyl-3-nitrobenzenesulfonamide
Figure imgf000052_0001
a) 4-fluoro-3-nitrobenzenesulfonyl chloride
1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65 °C. The resulting mixture was then heated to 100 °C for 18 h. The mixture was cooled to rt, poured over ice and extracted with CH2CI2. The combined organic layers were then washed with sat. aq. NaHC03, then brine, dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (55.3 g, 65%) as a brown oil. b) 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide
To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL) was added Et3N (150 mL, 1.08 mol). The mixture was cooled to -35 °C and ΟΗ3ΝΗ2·ΗΟΙ (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to rt and diluted with 1 :1 water/EtOAc. The organic layer was separated and washed with sat. aq. NaHC03, then brine, dried over MgS04, filtered, and concentrated in vacuo. The crude residue was purified via flash column chromatography (20%
EtOAc/petroleum ether) to afford the title compound (38 g, 90%) as a yellow solid.
PREPARATION 2
3-amino-4-fluoro-/V-methylbenzenesulfonamide
Figure imgf000053_0001
To a mixture of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (1 .6 g, 6.83 mmol) in THF (50 mL) under nitrogen was added Pd/C (0.600 g). The flask was then evacuated and recharged with H2. The resulting mixture was allowed to stir under a H2 atmosphere overnight at 50 °C. The mixture was then filtered and concentrated to afford the title compound (1.25 g, 89%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26 (q, J = 4.85 Hz, 1 H), 7.13 - 7.22 (m, 2H), 6.90 (ddd, J = 2.38, 4.27, 8.41 Hz, 1 H), 5.63 (s, 2H), 2.40 (d, J = 5.02 Hz, 3H); MS (m/z) 205.1 (M+H+).
PREPARATION 3
3-amino-/V-methyl-4-[4-(2,2,2-trifluoroethyl)-1-piperazinyl]benzenesulfonamide
Figure imgf000053_0002
a) /V-methyl-3-nitro-4-[4-(2,2,2-trifluoro
To a solution of 4-fluoro-A/-methyl-3-nitrobenzenesulfonamide (1.25 g, 5.36 mmol) and /'-Pr2NEt in THF (40 ml.) was added 1 -(2,2,2-trifluoroethyl)piperazine (1 g, 5.9 mmol). The resulting mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The organic layer was separated and washed with sat. aq. NaHC03 and brine, dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (1 .78 g, 87%) as a yellow solid. b) 3-amino-/V-methyl-4-[4-(2,2,2-trifluoroethyl)-1-piperazinyl]benzenesulfonamide
To a solution of A/-methyl-3-nitro-4-[4-(2,2,2-trifluoroethyl)-1- piperazinyl]benzenesulfonamide (1 .78 g, 4.65 mmol) in MeOH (80 mL) was added Pd/C (0.200 g). The system was alternatively evacuated and charged with hydrogen three times. After the final evacuation, the system was charged with hydrogen to 1000 psi and the resulting mixture stirred for 12 h. The mixture was then filtered and the solvent removed in vacuo to afford a deep colored oil. The crude material was purified via flash column chromatography (5% MeOH/CH2CI2) to afford the title compound (1 .01 g, 82%) as a brown solid. 1 H NMR (400 MHz, CD3OD-d4) δ ppm 7.19 (s, 1 H), 7.07 - 7.16 (m, 2H), 3.16 (q, J = 9.79 Hz, 2H), 2.95 - 3.03 (m, 4H), 2.89 (d, J = 4.52 Hz, 4H), 2.52 (s, 3H); MS (m/z) 353.1 (M+H+).
The following anilines were prepared from 4-fluoro-/V-methyl-3- nitrobenzenesulfonamide and the indicated amine using the procedures described Preparation 3:
MS
Aniline Product Amine in Step 1 Ή NMR
(m/z)
H NMR (400 MHz, DMSO- d6) δ ppm 7.03 - 7.10 (m,
3-amino-4-(dimethylamino)-/V- 230.2 2H), 7.00 (d, J = 8.28 Hz, dimethylamine
methylbenzenesulfonamide (M+H+) 1 H), 6.93 (dd, J = 2.13,
8.16 Hz, 1 H), 5.13 (s, 2H), 2.62 (s, 6H), 2.38 (d, J = 5.02 Hz, 3H)
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
PREPARATION 4
3-amino-/V-methyl-4-(methylthio)benzenesulfonamide
Figure imgf000057_0002
a) /V-methyl-4-(methylthio)-3-nitrobenzenesulfonamide
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (15 g, 64.01 mmol) in THF (150 mL) was added 20% CH3SNa (22.4 g, 64.01 mmol) dropwise. The resulting mixture was then stirred overnight. In the morning, the mixture was poured into EtOAc and water, the organic phase separated, dried over Na2S04, filtered and concentrated. The crude material was then purified via flash column chromatography (1 :1
EtOAc/petroleum ether) to afford the title compound (3.29 g, 19%) as a yellow solid. MS (m/z) 262.7 (M+H+). b) 3-amino-/V-methyl-4-(methylthio)benzenesulfonamide
To a solution of A/-methyl-4-(methylthio)-3-nitrobenzenesulfonamide (1.0 g, 3.81 mmol) in 10 mL of EtOH and 10 mL of NH4CI was added zinc dust (2.5 g, 3.81 mmol). The reaction mixture was stirred overnight at rt. The mixture was then filtered and diluted with EtOAc and water. The organic phase was separated, washed with water and brine, dried over MgS04, filtered, and concentrated to afford the title compound (0.500 g, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.06 (d, J = 8.03 Hz, 1 H), 6.86 (s, 1 H), 6.67 - 6.76 (m, 1 H), 5.28 (br. s, 2H), 2.17 (s, 3H), 2.21 (s, 3H); MS (m/z) 232.7 (M+H+). PREPARATION 5
/V-methyl-2,3-dihydro-1 H-indole-6-sulfonamide
Figure imgf000058_0001
a) 2,3-dihydro-1 H-indole-6-sulfonic acid
H2S04'S03 (20%, 21 ml_, 0.42 mmol) was cooled to 0 °C. Indoline (5.0 g, 0.042 mmol) was added dropwise such that the temperature of the reaction mixture did not rise above 35 °C. When the addition was complete the mixture was heated to 135 °C for 0.5 h. After cooling, the solution was poured into an ice bath at which time the product crystallized. The mixture was then filtered and washed with water and acetone to afford the title compound (6.9 g, 82%) as a white solid. b) 1 -acetyl-2,3-dihydro-1 H-indole-6-sulfonic acid
To a slurry of 2,3-dihydro-1 H-indole-6-sulfonic acid (6.9 g, 34.6 mmol) in AcOH (40 ml_), was added acetic anhydride (3.5 g, 34.6 mmol) and pyridine (15 ml_). The mixture was then heated to 100 °C for 24 h before it was cooled and concentrated to afford the title compound (8.8 g, 84%) as a brown oil. c) 1-acetyl-2,3-dihydro-1 H-indole-6-sulfonyl chloride
To a mixture of POCI3 (12.6 g, 153.33 mmol) and one drop of DMF in CH3CN (100 ml.) was added 1 -acetyl-2,3-dihydro-1 H-indole-6-sulfonic acid (8.8 g, 27.5 mmol). The mixture was heated to reflux for 1 h and then concentrated to afford a pale yellow oil. The oil was then poured onto ice and filtered to afford the title compound (7.0 g) as a brown solid. d) 1 -acetyl-/V-methyl-2,3-dihydro-1 H-indole-6-sulfonamide
To a solution of 1-acetyl-2,3-dihydro-1 /-/-indole-6-sulfonyl chloride (7.0 g, 27.0 mmol) in 100 ml. of CH2CI2 was added 30% aq. CH3NH2 dropwise at a rate such that the internal temperature of the reaction did not rise above 22 °C. The mixture was then stirred for 2 h. The solution was washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (1 :1 petroleum ether/EtOAc) to afford the title compound (5.0 g, 74%) as a brown solid. MS (m/z) 255.3 (M+H+). e) A/-methyl-2,3-dihydro-1 H-indole-6-sulfonamide
A slurry of 1 -acetyl-/V-methyl-2,3-dihydro-1 H-indole-6-sulfonamide (5.0 g, 19.7 mmol) in MeOH was purged with HCI gas for 30 min. The solution was then stirred at rt for 2 h before the solution was concentrated in vacuo. The resulting solid was dissolved in a sat. aq. solution of NaHC03 and EtOAc. The layers were separated and the organic layer washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude material was then purified via flash column chromatography (1 :1 EtOAc/petroleum ether) to afford the title compound (1 .49 g, 32%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.13 - 7.23 (m, 2H), 6.90 (dd, J = 1.51 , 7.53 Hz, 1 H),
6.77 - 6.83 (m, 1 H), 5.96 (s, 1 H), 3.44 - 3.54 (m, 2H), 2.97 (t, J = 8.66 Hz, 2H), 2.37 (d, J = 5.02 Hz, 3H); MS (m/z) 255.3 (M+H+).
PREPARATION 6
3-amino-/V-methyl-4-[(1-methylethyl)oxy]benzenesulfonamide
Figure imgf000059_0001
a) A/-methyl-4-[(1-methylethyl)oxy]-3-nitrobenzenesulfonamide
NaH (60% dispersion in oil, 0.440 g, 1 1 mmol) was added to 20 ml. of isopropanol and the resulting mixture stirred at rt. After 30 min, 4-fluoro-/V-methyl-3- nitrobenzenesulfonamide (2.34 g, 10 mmol) was added. The reaction mixture was then stirred at rt overnight. The mixture was poured into EtOAc and water. The organic phase was separated, dried over Na2S04, and concentrated in vacuo to afford the crude product. Purification via flash column chromatography (1 : 1 petroleum ether/ EtOAc) afforded the title compound (1 .6 g, 58%) as a yellow solid. MS (m/z) 274.7 (M+H+). b) 3-amino-/V-methyl-4-[(1 -methylethyl)oxy]benzenesulfonamide
To a mixture of A/-methyl-4-[(1 -methylethyl)oxy]-3-nitrobenzenesulfonamide (1 .6 g, 5.8 mmol) in EtOH (20 mL) under nitrogen was added Pd/C (0.160 g). The flask was then evacuated and recharged with H2 three times. The resulting mixture was allowed to stir under a H2 atmosphere overnight at rt. The mixture was then filtered and concentrated to afford the title compound (1 .1 g, 77%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.01 - 7.10 (m, 2H), 6.87 - 6.98 (m, 2H), 5.08 (br. s, 2H), 4.63 (dt, J = 5.93, 1 1 .98 Hz, 1 H), 2.34 - 2.41 (m, 3H), 1 .29 (d, J = 6.02 Hz, 6H); MS (m/z) 244.7 (M+H+). The following aniline was prepared from 4-fluoro-/V-methyl-3- nitrobenzenesulfonamide using the procedures analogous to those described in
Preparation 6:
Figure imgf000060_0001
PREPARATION 7
-4-[(2-hydroxyethyl)(methyl)amino]-/V-methylbenzenesulfonamide
Figure imgf000061_0001
a) 4-[(2-hydroxyethyl)(methyl)amino]-/V-methyl-3-nitrobenzenesulfonamide
To a solution of 3-amino-4-fluoro-/V-methylbenzenesulfonamide (2.0 g, 8.54 mmol) and /'-Pr2NEt (10 ml_, 57.4 mmol) in THF (80 ml.) at rt, was added 2-(methylamino)ethanol (0.77 g, 10.25 mmol). The resulting mixture was stirred at rt for 1 h. The solvent was then removed, the residue diluted with 1 :1 EtOAc/water. The organic layer was then separated and washed with sat. aq. NaHC03, dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (2.05 g, 83%) as a red oil. b) 3-amino-4-[(2-hydroxyethyl)(methyl)amino]-/\/-methylbenzenesulfonamide
To a solution of 4-[(2-hydroxyethyl)(methyl)amino]-/V-methyl-3- nitrobenzenesulfonamide (2.01 g, 6.95 mmol) in MeOH (80 ml_), was added zinc (1.82 g, 27.8 mmol) and NH4CI (2.6 g, 48.65 mmol in 70 ml. of water). The mixture was then warmed to 50 °C for 2 h. The mixture was filtered and then extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The residue was purified via flash column chromatography (3:1 EtOAc/petroleum ether) to afford the title compound (0.8 g, 48%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (q, J = 5.02 Hz, 1 H), 6.99 - 7.04 (m, 2H), 6.89 (dd, J = 2.13, 8.16 Hz, 1 H), 5.49 (s, 2H), 4.93 (t, J = 5.27 Hz, 1 H), 3.58 (q, J = 5.19 Hz, 2H), 2.86 (t, J = 5.27 Hz, 2H), 2.65 (s, 3H), 2.38 (d, J = 5.02 Hz, 3H); MS (m/z) 260.0 (M+H+). PREPARATION 8
5-amino-/\/-methyl-3-pyridinesulfonamide
Figure imgf000062_0001
a) 5-bromo-3-pyridinesulfonyl chloride
A mixture of 3-pyridinesulfonyl chloride hydrochloride (8.9 g, 44 mmol) and bromine (14 g, 88 mmol) was heated to 130 °C for 8 h. The mixture was cooled and used directly in the next step. b) 5-bromo-/V-methyl-3-pyridinesulfonamide
To CH3NH2 (50 ml. of a 23-30 weight percent in H20) at 0 °C, was added 5-bromo- 3-pyridinesulfonyl chloride (44 mmol). The mixture was then warmed to rt and stirred for 3 h. The mixture was then extracted with EtOAc and concentrated in vacuo. The crude material was combined with that from an additional experiment (10 mmol scale) run under identical conditions and washed with 10:1 hot petroleum ether/EtOAc to afford the title compound (2.4 g, 18% combined yield over two steps). c) 5-amino-/V-methyl-3-pyridinesulfonamide
A mixture of 5-bromo-/V-methyl-3-pyridinesulfonamide (2.4 g, 9.6 mmol), CuCI (0.100 g, 1.01 mmol), and NH4OH (5 ml.) was heated to 130 °C for 18 h in a sealed tube. The reaction mixture was then treated with sodium sulfide and extracted with EtOAc. The combined organic extracts were then concentrated in vacuo and the crude material washed with 20:5:3 hot petroleum ether/EtOAc/MeOH to afford the title compound (1.1 g, 61 %) as a brown solid. 1H N MR (400 MHz, DMSO-d6) δ ppm 8.1 1 (d, J = 2.51 Hz, 1 H), 8.04 (d, J = 1 .76 Hz, 1 H), 7.47 (br. s, 1 H), 7.24 (t, J = 2.13 Hz, 1 H), 5.83 (br. s, 2H), 2.44 (s, 3H); MS (m/z) 188.1 (M+H+). PREPARATION 9
-A/,4-dimethylbenzenesulfonamide
Figure imgf000063_0001
a) A/,4-dimethyl-3-nitrobenzenesulfonamide
A mixture of 4-methyl-3-nitrobenzenesulfonyl chloride (0.350 g, 1 .485 mmol) and DMAP (0.036 g, 0.297 mmol) in CH3NH2 (2.971 mL, 5.94 mmol of a 2 M solution in THF) was heated at reflux for 1 h. Additional CH3NH2 (2.97 mL, 5.94 mmol of a 2 M solution in THF) was added and the resulting mixture stirred at reflux for an additional 2 h. The reaction was then cooled, filtered, and the filtrate concentrated to afford the title compound. b) 3-amino-/V,4-dimethylbenzenesulfonamide
A mixture of A/,4-dimethyl-3-nitrobenzenesulfonamide (0.544 g, 2.36 mmol), Pd/C (0.251 g, 0.236 mmol) and HC02 «NH4 (0.745 g, 1 1.81 mmol) in EtOH was heated at 80 °C for 2 h. The reaction mixture was cooled, filtered through Celite® (washing with EtOH), and concentrated in vacuo to afford the title compound (0.459 g, 97%). 1H NMR (400 MHz, DMSO-de) δ ppm 7.15 (q, J = 4.85 Hz, 1 H), 7.10 (d, J = 7.78 Hz, 1 H), 7.03 (d, J = 1.76 Hz, 1 H), 6.84 (dd, J = 1.88, 7.65 Hz, 1 H), 5.33 (s, 2H), 2.38 (d, J = 5.02 Hz, 3H), 2.07 - 2.14 (m, 3H); MS (m/z) 201 .0 (M+H +). PREPARATION 10
3-amino-4-hydroxy-/V-methylbenzenesulfonamide
Figure imgf000063_0002
a) 4-hydroxy-/V-methyl-3-nitrobenzenesulfonamide
A suspension of 4-hydroxy-3-nitrobenzenesulfonyl chloride (0.749 g, 3.15 mmol) and DMAP (0.077 g, 0.630 mmol) in THF (7.880 mL) was treated with CH3NH2 (2 M in THF, 6.30 mL, 12.61 mmol). The resulting mixture was then stirred at rt overnight. The mixture was then filtered and the filtrate partitioned between CH2CI2 and sat. aq. NaHC03. The layers were separated by hydrophobic frit. The aqueous layer was then extracted with CH2CI2 at pH 7, pH 5 (twice), and pH 2. The pH 5 and pH 2 extracts were then combined and concentrated to afford the title compound (0.31 1 g, 42%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br. s, 1 H), 8.22 (d, J = 2.52 Hz, 1 H), 7.88 (dd, J = 2.27, 8.81 Hz, 1 H), 7.53 (q, J = 4.95 Hz, 1 H), 7.31 (d, J = 8.81 Hz, 1 H), 2.42 (d, J = 5.04 Hz, 3H); MS (m/z) 232.8 (M+H+). b) 3-amino-4-hydroxy-/V-methylbenzenesulfonamide
A solution of 4-hydroxy-/V-methyl-3-nitrobenzenesulfonamide (0.280 g, 1.206 mmol) in EtOH (0.269 mL) was added to a mixture of HC02*NH4 (0.380 g, 6.03 mmol) and Pd/C (0.128 g, 0.121 mmol) in EtOH (0.269 mL) and the reaction heated to 80 °C. Once the reaction mixture reached 80 °C, it was allowed to cool to rt and stand overnight. The mixture was then filtered through Celite® and concentrated to afford the title compound
(0.177 g, 73%) as a brown oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (br. s, 1 H), 7.00 (d, J = 2.01 Hz, 2H), 6.80 - 6.87 (m, 1 H), 6.75 (d, J = 8.28 Hz, 1 H), 4.97 (br. s, 2H), 2.35 (d, J = 4.77 Hz, 3H); MS (m/z) 202.9 (M+H+).
PREPARATION 1 1
3-amino-4-chloro-/V-methylbenzenesulfonamide
Figure imgf000064_0001
a) 4-chloro-/V-methyl-3-nitrobenzenesulfonamide
A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (10 g, 39.1 mmol) in THF (100 mL) was cooled to -40 °C before being treated with a solution of CH3NH2 «HCI (2.64 g, 39.1 mmol) in 10 mL of water followed by Et3N (5.44 mL, 39.1 mmol). The reaction mixture was stirred and allowed to warm to rt over 1 h before being partitioned between 350 mL EtOAc and 30 mL brine. The organic layer was washed twice with brine, dried over MgS04 and subjected to flash column chromatography (0-40% EtOAc/hexanes) to afford the title compound (6.38 g, 65%) as a light yellow solid. MS (m/z) 251.0 (M+H+). b) 3-amino-4-chloro-/V-methylbenzenesulfonamide
A solution of 4-chloro-/V-methyl-3-nitrobenzenesulfonamide (6.35 g, 25.3 mmol) in EtOH (150 mL) and water (50.0 mL) was treated with iron (14.15 g, 253 mmol) and NH4CI (13.55 g, 253 mmol) and heated at 90 °C for 4 h before being cooled and filtered through Celite®. The filter cake was washed with EtOAc and the combined filtrate was filtered again to remove precipitated NH4CI before being concentrated. The resulting crude material was partitioned between 350 mL EtOAc and 50 mL sat. aq. NaHC03. The organic layer was washed with brine, dried over MgS04, concentrated and subjected to flash column chromatography (0-15% EtOAc/CH2CI2) to afford the title compound (5.604 g, 100%) as a light yellow crystalline solid. 1H NMR (400 MHz, MeOD) δ ppm 7.39 (d, J=8.28 Hz, 1 H), 7.27 (d, J=2.26 Hz, 1 H), 7.03 (dd, J=8.28, 2.26 Hz, 1 H), 2.54 (s, 3 H). MS 221 .0 (M+H+).
PREPARATION 12
6-bromo-4-chloro-1 H-pyrrolo[2,3-c/]pyrimidine and 5,6-dibromo-4-chloro-1 H-pyrrolo[2,3- c/]pyrimidine
Figure imgf000065_0001
a) 6-bromo-4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c ]pyrimidine and 5,6-dibromo-4- chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c ]pyrimidine
To a solution of diisopropylamine (0.534 mL, 3.74 mmol) in THF (5 mL) at -78 °C was added n-BuLi (2.341 mL of a 1.6M solution in hexanes, 3.74 mmol) dropwise via syringe. The resultant pale yellow solution of LDA was allowed to warm to rt. A separate 100 mL round bottom flask was charged with 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3- c/]pyrimidine (1 g, 3.40 mmol) and THF (16.36 mL) under a nitrogen atmosphere. Once in solution, the flask was cooled to -78 °C and the LDA solution added dropwise. The resultant orange solution was stirred at -78 °C under nitrogen. After 45 min, a solution of 1 ,2-dibromotetrachloroethane (2.217 g, 6.81 mmol) in THF (4.91 mL) was added dropwise via syringe. After addition was complete, reaction mixture continued to stir at -78 °C under nitrogen for 1 .5 h. The reaction was quenched with sat. aq. NH4CI and warmed to rt. The mixture was then extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture of 6- bromo-4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c ]pyrimidine and 5,6-dibromo-4-chloro- 7-(phenylsulfonyl)-7H-pyrrolo[2,3-c ]pyrimidine was used in the next step without further purification. b) 6-bromo-4-chloro-1 /-/-pyrrolo[2,3-c ]pyrimidine and 5,6-dibromo-4-chloro-1 /-/- pyrrolo[2,3-c ]pyrimidine
KOf-Bu (1 .908 g, 17.00 mmol) was added to a dark orange solution of 6-bromo-4- chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c ]pyrimidine (1 .267 g, 3.4 mmol) in THF (34 mL) in a 250 mL round bottom flask. The orange suspension was then stirred at rt under nitrogen for 3.5 h. The reaction mixture was diluted with sat. aq. NaHC03 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified via flash column chromatography (10-40% EtOAc/hexanes) to afford mixtures of 6-bromo-4-chloro-1 /-/- pyrrolo[2,3-c ]pyrimidine (0.162 g, 21 % for two steps based on NMR integration) and 5,6- dibromo-4-chloro-1 /-/-pyrrolo[2,3-c ]pyrimidine (0.306 g, 29% for two steps based on NMR integration). MS (m/z) 233.7 (M+); MS (m/z) 31 1.6 (M+H+).
PREPARATION 13
1 , 1-dimethylethyl 4-chloro-1 /-/-pyrrolo[2,3-c ]pyrimidine-6-carboxylate
Figure imgf000067_0001
a) 1 ,1 -dimethylethyl 4-chloro-5-hydroxy-5,6-dihydro-1 /-/-pyrrolo[2,3-d]pyrimidine-6- carboxylate
To a suspension of 4,6-dichloro-pyrimidine-5-carbaldehyde (2 g, 1 1 mmol) in EtOH (50 mL) at rt was added glycine ferf-butyl ester (1 .894 g, 1 1 mmol) followed by Et3N (3.9 mL, 28 mmol). The reaction mixture was stirred at rt for 24 h. The mixture was then concentrated and the residue diluted with water and CH2CI2. The organic layer was collected, evaporated, and purified via flash column chromatography (0-90%
EtOAc/hexanes) to afford the title compound (1.38 g, 44.9%) as a mix of two isomers, a light yellow solid. MS (m/z) 272.1 (M+H+). b) 1 ,1 -dimethylethyl 4-chloro-1 H-pyrrolo[2,3-d]pyrimidine-6-carboxylate
To a solution of 1 , 1 -dimethylethyl 4-chloro-5-hydroxy-5,6-dihydro-1 /-/-pyrrolo[2,3- d]pyrimidine-6-carboxylate (1 .38 g, 5.06 mmol) in DMF (20 mL) at 0 °C was added NaH (0.186 g of a 60% dispersion in mineral oil, 4.64 mmol). The resulting mixture was stirred for 1 h. The reaction was quenched slowly with 2 mL of water and partitioned between 30 mL sat. aq. NH4CI solution and 250 mL EtOAc. The organic layer was washed with sat. aq. NH4CI (2 x 20 mL) then brine (30 mL), dried over MgS04 and concentrated to dryness. The resulting yellowish solid was suspended in 10 mL hexanes and filtered to afford the title compound (718 mg, 56%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.33 (br. s, 1 H), 8.74 (s, 1 H), 7.14 (s, 1 H), 1 .58 (s, 9H); MS (m/z) 254.1 (M+H+). PREPARATION 14
4-chloro-5-fluoro-1 /-/-pyrrolo[2,3-c ]pyrimidine
Figure imgf000068_0001
A mixture of 6-chloro-7-deazapurine (0.5 g, 3.26 mmol) and Selectfluor® (1.730 g, 4.88 mmol) in CH3CN (25 mL) was treated with AcOH (5 mL) and heated at 70 °C overnight before being cooled and concentrated. Toluene was added and the mixture was concentrated. The residue was dissolved in 1 :1 EtOAc/CH2CI2 and filtered through a pad of silica gel. The filtrate was concentrated and purified via flash column chromatography (20% EtOAc/CH2CI2) to afford the title compound (0.226 g, 41 %) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1 H), 8.60 - 8.66 (m, 1 H), 7.73 (t, J = 2.51 Hz, 1 H); MS (m/z) 171.9 (M+H+).
PREPARATION 15
5-bromo-4-chloro-1 /-/-pyrrolo[2,3-c/]pyri
Figure imgf000068_0002
A mixture of 4-chloro-1 H-pyrrolo[2,3-c ]pyrimidine (10 g, 65.1 mmol) in CH2CI2 (400 mL) at 25 °C was treated with NBS (13.91 g, 78 mmol) and stirred for 30 min before being concentrated. The resulting brown solid was triturated with water (-500 mL) and after drying, was triturated with EtOAc to afford the title compound (12.4 g, 73.7%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s, 1 H), 8.64 (s, 1 H), 7.97 (d, J = 2.76 Hz, 1 H); MS (m/z) 232.9 (M+H+).
PREPARATION 16
6-chloro-7-methyl-7-deazapurine
Figure imgf000068_0003
A mixture of 5-bromo-4-chloro-1 /-/-pyrrolo[2,3-c ]pyrimidine (1 g, 4.30 mmol) in THF (20 mL) at -78 °C was treated dropwise with n-BuLi (6.5 mL of 1 .6 M in hexanes, 10.40 mmol). After 15 min, iodomethane (0.807 mL, 12.91 mmol) was added and the mixture was stirred for 15 min at -78 °C before being quenched with the addition of water and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2S04, and concentrated to afford an off-white solid, which was triturated with MeOH to afford the title compound (0.33 g, 41 %) as an off-white solid. 1 H NMR (400 MHz, DMSO-c/6) δ ppm 12.25 (br. s, 1 H), 8.51 (s, 1 H), 7.44 (s, 1 H), 2.42 (s, 3 H). MS (m/z) 168.0 (M+H+).
The following deazapurine was prepared from 5-bromo-4-chloro-1 /-/-pyrrolo[2,3- c/]pyrimidine using the indicated alkyl halide and procedures analogous to those described in Preparation 16:
Figure imgf000069_0002
PREPARATION 17
4-chloro-6-(1 -pyrrolidinylcarbonyl)-1 H-pyrrolo[2,3-c/]pyrimidine
Figure imgf000069_0001
a) 4-chloro-1 /-/-pyrrolo[2,3-c ]pyrimidine-6-carboxylic acid
1 , 1 -dimethylethyl 4-chloro-1 H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (500 mg, 1 .971 mmol) was dissolved in TFA (10 mL, 130 mmol) and stirred for 1 h before being concentrated to afford the title compound (390 mg, 100%) as a yellow solid. MS (m/z) 198.0 (M+H+). b) 4-chloro-6-(1-pyrrolidinylcarbonyl)-1 H-pyrrolo[2,3-(^pyrimidine
A suspension of 4-chloro-1 /-/-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (390 mg, 1.974 mmol) in CH2CI2 (20 mL) was treated with oxalyl chloride (0.259 mL, 2.96 mmol) followed by 2 drops of DMF. The resulting mixture was stirred at rt for several hours until all solid dissolved and no more bubbling occurred. The reaction mixture was
concentrated, redissolved in 20 mL of CH2CI2 and treated with pyrrolidine (140 mg, 1 .974 mmol) and Et3N (0.550 mL, 3.95 mmol). The mixture was stirred at rt for 1 h before being concentrated and subjected to flash column chromatography (0-100% EtOAc/CH2CI2) to afford the title compound (132 mg, 26.7%) as a white solid. 1 H NMR (400 MHz, DMSO- cfe) δ ppm 13.06 (br. s, 1 H), 8.68 (s, 1 H), 7.05 (s, 1 H), 3.84 (t, J=6.53 Hz, 2 H), 3.56 (t, J=6.78 Hz, 2 H), 1.85 - 2.00 (m, 4 H). MS (m/z) 251 .0 (M+H+).
PREPARATION 18
4-chloro-6-[3-(trifluoromethyl)phenyl]-1 /-/-pyrrolo[2,3-c/]pyri
Figure imgf000070_0001
a) 4-chloro-7-(phenylsulfonyl)-6-[3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c ]pyrimidine
A mixture of 6-bromo-4-chloro-7-(phenylsulfonyl)-7/-/-pyrrolo[2,3-d]pyrimidine (1.97 g, 4.34 mmol), [3-(trifluoromethyl)phenyl]boronic acid (0.823 g, 4.34 mmol) and K2C03 (0.959 g, 6.94 mmol) in 1 ,4-dioxane (36 mL) and water (12.00 mL) was purged with nitrogen for 10 min before being treated with PdCI2(dppf)«CH2CI2 (0.5 g, 0.612 mmol). The mixture was stirred at 82 °C for 3 h before being cooled and partitioned between 200 mL EtOAc and 30 mL brine. The organic layer was washed with brine, dried over MgS04, concentrated, and subjected to flash column chromatography (EtOAc/hexanes 0-35%) to afford the title compound (0.893 g, 47.0%) as a white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 8.90 (s, 1 H), 7.89 - 7.96 (m, 5 H), 7.78 (t, J=7.53 Hz, 2 H), 7.61 - 7.69 (m, 2 H), 7.16 (s, 1 H). MS (m/z) 438.0 (M+H+). b) 4-chloro-6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3-(^pyrimidine
A solution of 4-chloro-7-(phenylsulfonyl)-6-[3-(trifluoromethyl)phenyl]-7/-/- pyrrolo[2,3-d]pyrimidine (500 mg, 1.142 mmol) in dry THF (20 mL) was treated with
KOf-Bu (641 mg, 5.71 mmol) at 0 °C before being warmed to rt. After 30 min, the mixture was diluted with 50 mL of sat. aq. Na2C03 and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine, dried over MgS04, and concentrated to afford the title compound (345 mg, 100%) as a light brown solid. MS (m/z) 298.0 (M+H+).
PREPARATION 19
5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-1 -methyl-1 H-pyrazole
Figure imgf000071_0001
To a solution of 1-methylpyrazole (4.1 g, 50 mmol) in THF (100 mL) at 0 °C was added n-BuLi (2.2 M in THF, 25 mL, 55 mmol). The reaction solution was stirred for 1 h at rt and then cooled to -78 °C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmol). After 15 min at -78 °C, the reaction was allowed to warm to 0 °C over 1 h. The reaction was diluted with sat. aq. NH4CI solution and extracted with CH2CI2. The organic fractions were washed with H20 (2 x 100 mL), dried over Na2S04 and concentrated in vacuo to afford the title compound (8.0 g, 77%) as a tan solid. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), 1 .41 (s, 12H).
PREPARATION 20
3-amino-/V-methyl-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfon
Figure imgf000072_0001
a) phenylmethyl [(4-fluoro-3-nitrophenyl)sulfonyl]methylcarbamate
A solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (2 g, 8.54 mmol) in THF (20 mL) was treated with Et3N (2.380 mL, 17.08 mmol) followed by dropwise addition of benzyl chloroformate (3.75 mL, 1 1.10 mmol). The mixture was stirred at 25 °C for 5 h before being concentrated. The residue was treated with water and extracted with CH2CI2. The organic extracts were washed with brine, dried over sodium sulfate, concentrated, and subjected to flash chromatography (25-50% EtOAc-hexanes) to give a yellow solid, which was suspended in EtOAc-hexanes, collected by filtration, and washed with hexanes to give phenylmethyl [(4-fluoro-3-nitrophenyl)sulfonyl]methylcarbamate (1 g, 32%) as a white solid. MS (m/z) 391 .0 (M+Na+). b) phenylmethyl methyl({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl) carbamate A solution of phenylmethyl [(4-fluoro-3-nitrophenyl)sulfonyl]methylcarbamate (1 g,
2.71 mmol) in THF (10 mL) at 25 °C was treated with 2,2,2-trifluoroethylamine (0.592 g, 5.97 mmol) and stirred for 20 h before being concentrated to give a yellow oil, which was dissolved in EtOAc/hexanes. A yellow precipitate formed, which was collected by filtration and washed with hexanes to give phenylmethyl methyl({3-nitro-4-[(2,2,2- trifluoroethyl)amino]phenyl}sulfonyl)carbamate (1 .07 g, 88%) as a yellow solid. MS (m/z) 448.1 (M+H+). c) phenylmethyl methyl({4-[methyl(2,2,2-trifluoroethyl)amino]-3-nitrophenyl}sulfonyl) carbamate
A solution of phenylmethyl methyl({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl} sulfonyl)carbamate (1 g, 2.24 mmol) in DMF (1 mL) at 25 °C was treated with NaH (0.179 g, 4.47 mmol) and stirred for 2 min before being treated with iodomethane (0.42 mL, 6.71 mmol). After 1 hour, the mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over sodium sulfate, concentrated, and subjected to flash chromatography (10-35% EtOAc-hexanes) to give phenylmethyl methyl({4-[methyl(2,2,2-trifluoroethyl)amino]-3-nitrophenyl}sulfonyl) carbamate (539 mg, 52%) as a yellow oil. MS (m/z) 462.1 (M+H+). d) 3-amino-/V-methyl-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide A solution of phenylmethyl methyl({4-[methyl(2,2,2-trifluoroethyl)amino]-3- nitrophenyl}sulfonyl)carbamate (539 mg, 1 .17 mmol) in MeOH (10 mL) at 25 °C was treated with 10% Pd/C (124 mg, 0.1 17 mmol) and stirred under an atmosphere of hydrogen (balloon) overnight before being filtered through celite. The filtrate was again filtered through a 0.45 micron syringe filter and concentrated to give 3-amino-/V-methyl-4- [methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide (320 mg, 92%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14 - 7.20 (m, 2 H), 7.12 (d, J=2.26 Hz, 1 H), 6.95 (dd, J=8.28, 2.26 Hz, 1 H), 5.23 (s, 2 H), 3.82 (q, J=9.87 Hz, 2 H), 2.83 (s, 3 H), 2.39 (d, J=5.02 Hz, 3 H). MS (m/z) 298.0 (M+H+).
PREPARATION 21
3-amino-/V-methyl-4-[(trifluoromethyl)oxy]benzenesulfonamide
Figure imgf000073_0001
a) 3-nitro-4-[(trifluoromethyl)oxy]benzenesulfonyl chloride
Chlorosulfonic acid (6.47 mL, 97 mmol) was added to 2- trifluoromethylnitrobenzene (2.0 g, 9.66 mmol) and the mixture was heated to 100 °C for 24 h before being cooled to rt and poured onto ice and extracted with EtOAc. The combined organic extract was washed with brine, dried over sodium sulfate, and concentrated to give 3-nitro-4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (2.95 g, 100%) as a brown oil. b) A/-methyl-3-nitro-4-(trifluoromethoxy)benzenesulfonamide
CH3NH2 in EtOH, 33 wt% (2.405 mL, 19.32 mmol) was added dropwise to a solution of 3-nitro-4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (2.95 g, 9.66 mmol) in THF (45.9 ml) at 0 °C and the mixture was stirred at 0 °C for 4 h before being quenched with the addition of 2N HCI and extracted with EtOAc. The combined organic extract was washed with brine, dried over sodium sulfate, concentrated, and subjected to flash chromatography (0-100% EtOAc-hexanes) to give A/-methyl-3-nitro-4- (trifluoromethoxy)benzenesulfonamide (1 .16g, 40%) as a yellow solid. MS (m/z) 301 .0 (M+H+). c) 3-amino-/V-methyl-4-[(trifluoromethyl)oxy]benzenesulfonamide
A mixture of A/-methyl-3-nitro-4-[(trifluoromethyl)oxy]benzenesulfonamide (100 mg, 0.33 mmol) in MeOH (5 mL) was treated with 10% Pd/C (35.4 mg, 0.033 mmol) and stirred under an hydrogen atmosphere (balloon) for 24 h before being filtered and concentrated. The residue was dissolved in EtOH (2.5 mL) and treated with a solution of ammonium chloride (178 mg, 3.33 mmol) in water (1 mL) followed by zinc dust (218 mg, 3.33 mmol) and stirred at 25 °C for 1 h before filtering. The filtrate was diluted with water and extracted with EtOAc and the organic extracts were washed with brine, dried over sodium sulfate, and concentrated to give 3-amino-/V-methyl-4-
[(trifluoromethyl)oxy]benzenesulfonamide (80 mg, 89%) as a light brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.39 (q, J=4.77 Hz, 1 H), 7.31 (dd, J=8.53, 1.51 Hz, 1 H), 7.24 (d, J=2.26 Hz, 1 H), 6.92 (dd, J=8.41 , 2.38 Hz, 1 H), 5.92 (s, 2 H), 2.43 (d, J=4.77 Hz, 3 H). MS (m/z) 271 .0 (M+H+). EXAMPLE 1
3-[(5-bromo-1 H-pyrrolo[2,3-(^pyrimidin-4-yl)amino]-/V-methyl-4- (methyloxy)benzenesulfonamide
Figure imgf000075_0001
To a solution of 5-bromo-4-chloro-1 /-/-pyrrolo[2,3-d]pyrimidine (0.75 g, 3.24 mmol) and 3-amino-/V-methyl-4-(methyloxy)benzenesulfonamide (0.70 g, 3.24 mmol) in 1 ,4- dioxane (35 mL) stirred under nitrogen was added AcOH (0.93 mL, 16.18 mmol). The reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was concentrated in vacuo. The residue was then triturated in CH2CI2 to afford the title compound (1.30 g, 96%) as an off-white solid. LCMS (ES) m/e 413 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.39 (s, 1 H), 9.27 (s, 1 H), 8.83 (s, 1 H), 8.42 (s, 1 H), 7.61 (d, J=2.4 Hz, 1 H) 7.47 (m, 1 H) 7.36 (m, 1 H) 7.29 (d, J= 8.8 Hz, 1 H) 4.06 (s, 3H) 2.44 (d, J = 4.8 Hz, 3H).
EXAMPLE 2
3-[(5-bromo-1 /-/-pyrrolo[2,3-c/]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide
Figure imgf000075_0002
To a solution of 5-bromo-4-chloro-1 H-pyrrolo[2,3-d]pyrimidine (0.67 g, 2.87 mmol) and 3-amino-/V-methyl-4-[(1 -methylethyl)oxy]benzenesulfonamide (0.70 g, 2.87 mmol) in 1 ,4-dioxane (35 mL) stirred under nitrogen was added AcOH (0.82 mL, 14.33 mmol). The reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography (90:9:1
CHCI3/MeOH/NH4OH). The resulting solid was then triturated in CH2CI2 to afford the title compound (1.10 g, 80%) as a grey solid. LCMS (ES) m/e 442 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (s, 1 H), 9.27 (s, 1 H), 8.83 (s, 1 H), 8.43 (s, 1 H), 7.64 (d, J=2.4 Hz, 1 H), 7.45 (m, 1 H), 7.34 (m, 1 H), 7.32 (d, J= 8.8 Hz, 1 H), 4.92 (m, 1 H), 2.49 (s, 3H), 1 .40 (d, J = 6.0 Hz, 6H).
EXAMPLE 3
3-{[5-(2-furanyl)-1 H-pyrrolo[2,3-c/]pyrimidin-4-yl]amino}-/V-methyl-4
(methyloxy)benzenesulfonamide
Figure imgf000076_0001
A mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (0.20 g, 0.48 mmol), 2-furanylboronic acid (0.27 g, 2.43 mmol), Pd(f-Bu3P)2 (0.025 g, 0.05 mmol) and 2 M aq. K2C03 (1.21 mL, 2.43 mmol) in 1 ,4- dioxane (10 mL) was heated at 150 °C under microwave conditions for 40 min. The reaction material was purified by flash column chromatography (1 % NH4OH / 9% MeOH / 90% CHCI3). The resulting solid was triturated with MeOH to afford the title compound (130 mg, 66.4%) as an off-white solid. LCMS (ES) m/e 400 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (s, 1 H), 9.39 (s, 1 H), 9.24 (s, 1 H), 8.43 (s, 1 H), 7.87 (s, 1 H), 7.77 (s, 1 H), 7.44 (m, 1 H), 7.34 (m, 1 H), 7.28 (d, J= 8.4 Hz, 1 H), 6.76 (m, 1 H), 6.71 (m, 1 H), 4.02 (s, 3H), 2.49 (d, J = 5.2 Hz, 3H).
EXAMPLE 4
3-{[5-(2-furanyl)-1 H-pyrrolo[2,3-c ]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide
Figure imgf000076_0002
A mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide (0.20 g, 0.42 mmol), 2-furanylboronic acid (0.24 g, 2.1 mmol), Pd(f-Bu3P)2 (0.021 g, 0.042 mmol) and 2 M aq. K2C03 (1 .05 mL, 2.1 mmol) in 1 ,4-dioxane (10 mL) was heated at 150 °C under microwave conditions for 40 min. The reaction solution was concentrated in vacuo and purified by flash column chromatography (1 % NH4OH / 9% MeOH / 90% CHCI3). The solid product was triturated with Et20 to afford the title compound (100 mg, 55.2%) as off white solid. LCMS (ES) m/e 428 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (s, 1 H), 9.01 (s, 1 H), 8.76 (s, 1 H), 8.37 (s,
1 H), 7.79 (s, 1 H), 7.75 (s, 1 H), 7.41 (m, 1 H), 7.30 (m, 3H), 6.75 (d, J= 3.2 Hz, 1 H), 6.69 (d, J = 2.0 Hz, 1 H), 4.80 (m, 1 H), 2.49 (m, 3H), 1.28 (d, J = 6.0 Hz, 6H).
EXAMPLE 5
4-(dimethylamino)-3-{[5-(2-furanyl)-1 H-pyrrolo[2,3-c ]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide
Figure imgf000077_0001
A mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-
/V-methylbenzenesulfonamide (0.20g, 0.47 mmol), 2-furanylboronic acid (0.26 g, 2.35 mmol), Pd(f-Bu3P)2 (0.024 g, 0.047 mmol) and 2 M aq. K2C03 (1.18 mL, 2.35 mmol) in 1 ,4-dioxane (10 mL) was heated at 150 °C under microwave conditions for 40 min. The reaction solution was concentrated in vacuo and purified by flash column chromatography (1 % NH4OH / 9% MeOH / 90% CHCI3). The solid product was triturated with MeOH to afford the title compound (80 mg, 39%) as an off white solid. LCMS (ES) m/e 428 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (s, 1 H), 9.20 (s, 1 H), 9.15 (s, 1 H), 8.41 (s, 1 H), 7.79 (s, 1 H), 7.74 (s, 1 H), 7.41 (m, 1 H), 7.36 (m, 3H), 6.72 (m, 2H), 2.64 (s, 6H), 2.49 (m, 3H).
EXAMPLE 6
/V-methyl-4-(methyloxy)-3-{[5-(1^
yl]amino}benzenesulfonamide
Figure imgf000078_0001
A mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (0.30 g, 0.73 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.15 g, 0.73 mmol), Pd(f-Bu3P)2 (0.037 g, 0.073 mmol) and 2 M aq. K2C03 (1.82 ml_, 3.64 mmol) in 1 ,4-dioxane (10 ml.) was heated at
150 °C under microwave conditions for 40 min. The reaction material was purified by flash column chromatography (1 % NH4OH / 9% MeOH / 90% CHCI3). The resulting solid was triturated with MeOH to afford the title compound (120 mg, 30%) as an off-white solid. Reverse phase HPLC (5-90% H20/CH3CN) was used for final purification.
LCMS (ES) m/e 414 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s, 1 H), 9.28 (s, 1 H), 8.42 (s, 1 H), 8.06 (s, 1 H), 7.94 (s, 1 H), 7.41 (s, 1 H), 7.39 (m, 1 H), 7.33 (m, 1 H), 7.29 (s, 1 H), 7.19 (d, J = 8.8 Hz, 1 H), 6.72 (m, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 2.44 (m, 3H).
EXAMPLE 7
A/-methyl-4-(4-morpholinyl)-3-(1 /-/-pyrazolo[3,4-c/]pyrimidin-4-ylamino)benzenesulfonamide
Figure imgf000078_0002
To a solution of 4-chloro-1 /-/-pyrazolo[3,4-d]pyrimidine (250 mg, 1.62 mmol) in DMF (10 mL) were added 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (250 mg, 1 .62 mmol), and AgOTf (416 mg, 1.62 mmol). The reaction mixture was stirred at 80 °C for 16 h under nitrogen. The reaction mixture was diluted with aq. NaHC03 and extracted with CH2CI2. The organic layer was separated, dried over Na2S04, and concentrated in vacuo. Purification by flash column chromatography (CHCI3/MeOH/NH4OH, 90:9:1 ) afforded the title compound (410 mg, 64%) as an off-white solid. LCMS (ES) m/e 390 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.38 (s, 1 H), 8.29 (s, 1 H), 7.92 (s, 1 H), 7.83 (br s, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.8 Hz, 1 H), 3.68 (m, 4H), 3.05 (m, 4H), 2.59 (s, 3H).
EXAMPLE 8
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide
Figure imgf000079_0001
To 3-amino-/V-methyl-4-(4-morpholinyl)benzenesulfonamide (1.39 g, 5.14 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (1.0 g, 4.28 mmol) in 1 ,4-dioxane (60 mL) was added AgOTf (1.32 g, 5.14 mmol), and the reaction mixture was stirred at 80 °C in a sealed flask overnight. The reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (1 .5 g, 74.8%) as an off white solid. LCMS (ES) m/e 468,470 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.22 (s, 1 H), 9.15 (s, 1 H), 9.1 1 (d, J = 1 .77 Hz, 1 H), 8.54 (s, 1 H), 7.52 - 7.59 (m, 2H), 7.49 (d, J = 5.05 Hz, 1 H), 3.82 - 3.92 (m, 4H), 2.90 - 3.01 (m, 4H), 2.47 (d, J = 5.05 Hz, 3H).
EXAMPLE 9
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide
Figure imgf000079_0002
To a solution of 3-amino-4-(dimethylamino)-/V-methylbenzenesulfonamide (200 mg, 0.87 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (170 mg, 0.73 mmol) in 1 ,4-dioxane (10 mL) was added AgOTf (262 mg, 1.02 mmol). The reaction mixture was stirred at 80 °C in a sealed tube overnight. The reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCIs) / CHCI3 as eluent to afford the title compound (98 mg, 31.6%) as an off white solid. LCMS (ES) m/e 426,428 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.19 (s, 1 H), 9.44 (s, 1 H), 9.17 (s, 1 H), 8.56 (s, 1 H), 7.51 (s, 2H), 7.45 (d, J = 5.05 Hz, 1 H), 2.77 (s, 6H), 2.46 (d, J = 5.05 Hz, 3H).
EXAMPLE 10
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide
Figure imgf000080_0001
To a solution of 3-amino-/V-methyl-4-(methyloxy)benzenesulfonamide (189 mg,
0.87 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (170 mg, 0.73 mmol) in 1 ,4-dioxane (10 mL) was added AgOTf (262 mg, 1 .02 mmol). The reaction mixture was stirred at 80 °C in a sealed tube overnight. The reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (1 16 mg, 38.5%) as an off white solid. LCMS (ES) m/e 413, 415 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.21 (br. s, 1 H), 9.15 (d, J = 2.27 Hz, 1 H), 8.86 (s, 1 H), 8.55 (s, 1 H), 7.55 (dd, J = 2.40, 8.46 Hz, 1 H), 7.41 (d, J = 5.05 Hz, 1 H), 7.34 (d, J = 8.59 Hz, 1 H), 4.07 (s, 3H), 2.44 (d, J = 5.05 Hz, 3H).
EXAMPLE 1 1
/V-methyl-4-(4-morpholinyl)-3-[(3-phenyl-1 H-pyrazolo[3,4-d]pyrimidin-4- yl)amino]benzenesulfonamide
Figure imgf000081_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide (250 mg, 0.53 mmol), phenylboronic acid (260 mg, 2.14 mmol), PdCI2(dppf)«CH2CI2 (87 mg, 0.107 mmol) and 2 M aq. K2C03 (1.3 mL, 2.67 mmol) in 1 ,4-dioxane (3 mL) in a sealed tube was heated at 150 °C under microwave conditions for 30 min. The reaction materials were concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (1 12 mg, 45%) as a light tan solid. LCMS (ES) m/e 466 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 14.04 (s, 1 H), 9.02 (d, J = 2.02 Hz, 1 H), 8.54 (s, 1 H), 8.18 (s, 1 H), 7.78 - 7.84 (m, 2H), 7.56 - 7.69 (m, 3H), 7.44 - 7.51 (m, 2H), 7.35 (d, J = 8.34 Hz, 1 H), 3.05 (br. s, 4H), 2.62 (t, J = 4.29 Hz, 4H), 2.48 - 2.50 (m, 3H).
EXAMPLE 12
3-{[3-(3-chlorophenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide
Figure imgf000081_0002
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide (250 mg, 0.53 mmol), (3-chlorophenyl)boronic acid (167 mg, 1 .07 mmol), PdCI2(dppf)«CH2CI2 (87 mg, 0.1 1 mmol), and 2 M aq. K2C03 (0.80 mL, 1.60 mmol) in 1 ,4-dioxane (3 mL) was purged with nitrogen for 5 min, then was heated at 90 °C overnight. (3-chlorophenyl)boronic acid (167 mg, 1.07 mmol), PdCI2(dppf)«CH2CI2 (87 mg, 0.1 1 mmol), and 2 M aq. K2C03 (0.80 mL, 1 .60 mmol) were added to the reaction mixture, which was heated at 90 °C for another day. The organic layer was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to get 75 mg of a tan solid, which was further purified by reverse phase HPLC using 10- 80% CH3CN/water (0.1 % TFA mobile phase). The resulting TFA salt was neutralized with NaHC03, then extracted into EtOAc. The organic extract was dried over Na2S04 and then concentrated to afford the title compound (32 mg, 12%) as an off-white solid. LCMS(ES) m/e 500 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.14 (br. s, 1 H), 9.05 (d, J = 2.27 Hz, 1 H), 8.56 (s, 1 H), 8.18 (s, 1 H), 7.88 (s, 1 H), 7.75 - 7.81 (m, 1 H), 7.65 - 7.71 (m, 2H), 7.46 - 7.52 (m, 2H), 7.38 (d, J = 8.59 Hz, 1 H), 3.13 (br. s, 4H), 2.66 (t, J = 4.17 Hz, 4H), 2.50 (br. s, 3H).
EXAMPLE 13
A/-methyl-3-[(3-methyl-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(4- morpholinyl)benzenesulfonamide
Figure imgf000082_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide (200 mg, 0.43 mmol), trimethylboroxine (0.30 mL, 2.14 mmol), PdCI2(dppf)«CH2CI2 (35 mg, 0.04 mmol) and 2 M aq. K2C03 (1.07 mL, 2.13 mmol) in 1 ,4-dioxane (3 mL) was heated at 150 °C under microwave conditions for 30 min.
Additional trimethylboroxine (0.15 mL, 1 .07 mmol), PdCI2(dppf)«CH2CI2 (17 mg, 0.02 mmol) and 2 M aq. K2C03 (0.53 mL, 1.07 mmol) were added to the reaction mixture, which was heated at 150 °C under microwave conditions for an additional 20 min. The organic portion was concentrated onto silica gel and purified by flash column
chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (64 mg, 37%) as white solid. LCMS(ES) m/e 404 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.40 (br. s, 1 H), 9.09 (d, J = 2.02 Hz, 1 H), 8.93 (s, 1 H), 8.45 (s, 1 H), 7.55 - 7.60 (m, 1 H), 7.45 - 7.54 (m, 2H), 3.72 - 3.80 (m, 4H), 2.91 - 2.99 (m, 4H), 2.80 (s, 3H), 2.46 (d, J = 4.80 Hz, 3H).
EXAMPLE 14
3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]am
morpholinyl)benzenesulfonamide
Figure imgf000083_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide (150 mg, 0.32 mmol), 2-furanylboronic acid (179 mg, 1.60 mmol), PdCI2(dppf)«CH2CI2 (26 mg, 0.03 mmol) and 2 M aq. K2C03 (0.80 mL, 1.60 mmol) in 1 ,4-dioxane (3 mL) was heated at 150 °C under microwave conditions for 30 min. The organic portion was concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford 50 mg of an off-white solid. The solid was further purified by reverse phase HPLC using 10-80% CH3CN/water (0.1 % TFA mobile phase). The resulting TFA salt was neutralized with aq. NaHC03, then extracted into EtOAc. The organic extract was dried over Na2S04 and concentrated to afford the title compound (40 mg, 27%) as an off-white solid. LCMS (ES) m/e 456 (M+H)+; 1H NMR (400 MHz, DMSO-d6) 5 ppm 14.09 (br. s, 1 H), 9.15 (s, 1 H), 8.67 (d, J = 2.02 Hz, 1 H), 8.46 (s, 1 H), 8.10 (s, 1 H), 7.52 - 7.60 (m, 1 H), 7.44 (q, J = 4.63 Hz, 1 H), 7.39 (d, J = 8.59 Hz, 1 H), 7.12 (d, J = 3.28 Hz, 1 H), 6.79 - 6.87 (m, 1 H), 3.49 (br. s, 4H), 2.88 (br. s, 4H), 2.47 (d, J = 4.80 Hz, 3H). EXAMPLE 15
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[ethyl(2-hydroxyeth
methylbenzenesulfonamide
Figure imgf000084_0001
To 3-amino-4-[ethyl(2-hydroxyethyl)amino]-/V-methylbenzenesulfonamide (221 mg, 0.81 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (180 mg, 0.77 mmol) in 1 ,4-dioxane (10 ml.) was added AgOTf (258 mg, 1.0 mmol). The reaction mixture was stirred at 80 °C in a sealed tube overnight. The reaction materials were concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH4OH / 9% MeOH / 90% CHCIs) / CHCI3 as eluent to afford the title compound (43 mg, 12%) as an off-white solid. LCMS(ES) m/e 470,472(M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.18 (br. s, 1 H), 9.83 (s, 1 H), 9.22 (d, J = 2.02 Hz, 1 H), 8.55 (s, 1 H), 7.57 - 7.63 (m, 1 H), 7.43 - 7.54 (m, 2H), 4.53 (t, J = 5.18 Hz, 1 H), 3.39 - 3.48 (m, 2H), 3.08 - 3.20 (m, 4H), 2.48 (d, J = 5.05 Hz, 3H), 0.95 (t, J = 7.07 Hz, 3H).
EXAMPLE 16
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-{ethyl[2-(methyloxy)ethyl]amino}-/\/- methylbenzenesulfonamide
Figure imgf000084_0002
To 3-amino-4-{ethyl[2-(methyloxy)ethyl]amino}-/\/-methylbenzenesulfonamide (233 mg, 0.81 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (180 mg, 0.77 mmol) in 1 ,4-dioxane (10 mL) was added AgOTf (258 mg, 1.0 mmol). The reaction mixture was stirred at 80 °C in a sealed tube overnight. The reaction materials were concentrated onto Celite® and purified by flash column chromatography using 0-60% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (42 mg, 1 1 %) as an off-white solid. LCMS(ES) m/e 484,486 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.19 (s, 1 H), 9.87 (s, 1 H), 9.24 (d, J = 2.02 Hz, 1 H), 8.55 (s, 1 H), 7.62 (d, J = 8.34 Hz, 1 H), 7.43 - 7.54 (m, 2H), 3.30 - 3.33 (m, 2H), 3.1 1 - 3.24 (m, 4H), 3.05 (s, 3H), 2.48 (d, J = 5.05 Hz, 3H), 0.95 (t, J = 7.07 Hz, 3H).
EXAMPLE 17
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4- (methyloxy)benzenesulfonamide
Figure imgf000085_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (222 mg, 0.484 mmol), 3-furanylboronic acid (271 mg, 2.42 mmol), PdCI2(dppf)«CH2CI2 (39.5 mg, 0.048 mmol) and 2 M aq. K2C03 (1 .21 mL, 2.42 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated with Celite®. The residue was purified by flash column chromatography using 40-90% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (129 mg, 66%) as an off white solid. LCMS(ES) m/e 401 (M+H)+; 1H NMR
(400 MHz, DMSO-de) δ ppm 13.97 (br. s, 1 H), 9.29 (d, J = 2.27 Hz, 1 H), 8.57 (s, 1 H), 8.30 (s, 1 H), 8.35 (s, 1 H), 8.05 (t, J = 1.64 Hz, 1 H), 7.48 (dd, J = 2.27, 8.59 Hz, 1 H), 7.39 (d, J = 5.05 Hz, 1 H), 7.26 (d, J = 8.59 Hz, 1 H), 6.96 (s, 1 H), 3.91 (s, 3H), 2.43 (d, J = 5.05 Hz, 3H).
EXAMPLE 18
3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4- (methyloxy)benzenesulfonamide
Figure imgf000085_0002
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (222 mg, 0.48 mmol), 2-furanylboronic acid (271 mg, 2.42 mmol), PdCI2(dppf)«CH2CI2 (39 mg, 0.05 mmol) and 2 M aq. K2C03 (1.21 mL, 2.42 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (81 mg, 41 %) as off white solid. LCMS(ES) m/e 401 (M+H)+; 1 H NMR (400 MHz, DMSO-de) δ ppm 14.12 (br. s, 1 H), 9.72 (s, 1 H), 9.39 (d, J = 2.27 Hz, 1 H), 8.56 (s, 1 H), 8.03 (d, J = 1.01 Hz, 1 H), 7.53 (dd, J = 2.27, 8.59 Hz, 1 H), 7.33 - 7.42 (m, 2H), 7.10 (d, J = 3.03 Hz, 1 H), 6.84 (dd, J = 1.77, 3.54 Hz, 1 H), 4.09 (s, 3H), 2.45 (d, J = 5.05 Hz, 3H).
EXAMPLE 19
A/-methyl-3-{[3-(5-methyl-2-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-
(methyloxy)benzenesulfonamide
Figure imgf000086_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (222 mg, 0.48 mmol), (5-methyl-2-furanyl)boronic acid (244 mg, 1.94 mmol), PdCI2(dppf)«CH2CI2 (39 mg, 0.05 mmol) and 2 M aq. K2C03 (1.2 mL, 2.42 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 40-90% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (120 mg, 59%) as an off- white solid. LCMS(ES) m/e 415 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 14.02 (br. s, 1 H), 9.16 (s, 1 H), 8.96 (d, J = 2.27 Hz, 1 H), 8.49 (s, 1 H), 7.55 (dd, J = 2.27, 8.59 Hz, 1 H), 7.38 (d, J = 5.05 Hz, 1 H), 7.34 (d, J = 8.84 Hz, 1 H), 6.97 (d, J = 3.28 Hz, 1 H), 6.42 (dd, J = 1.01 , 3.28 Hz, 1 H), 3.99 (s, 3H), 2.42 - 2.48 (m, 6H). EXAMPLE 20
3-[(3-bromo-1 H-pyrazolo[3,4-o0pyrimidin-4-yl)amino]-/V-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide
Figure imgf000087_0001
a) 3-bromo-4-chloro-1-(phenylsulfon -1 H-pyrazolo[3,4-c ]pyrimidine
Figure imgf000087_0002
To a dry 500 mL flask was added 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (4 g, 17.13 mmol) in THF (160 mL). DMF (10 mL) was added and the stirred contents were cooled to 0 °C. NaH (60% dispersion in oil, 0.82 g, 20 mmol) was added portionwise and the mixture was stirred for 15 min. Benzene sulfonyl chloride (2.4 mL, 18.8 mmol) was added dropwise via syringe. After stirring for 15 min, the reaction vessel was removed from an ice bath. After 2 h, the contents were poured onto ice-water (50 mL), and stirred for 30 min. The white precipitate was filtered and washed with water to afford 4.38 g of a white solid. The mother liquor was concentrated down, extracted thrice with EtOAc and evaporated to dryness. The residue was triturated with EtOAc to afford an additional 1.3 g of the title compound. A total weight of 5.68 g of title compound was obtained (89%). LCMS(ES) m/e 373, 375 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.1 1 (s, 1 H), 8.1 1 (dd, J = 1.14, 8.46 Hz, 2H), 7.84 (s, 1 H), 7.71 (d, J = 8.34 Hz, 2H).
b) 3-{[3-bromo-1-(phenylsulfonyl)-1 H-pyrazolo^
methylethyl)oxy]benzenesulfonamide
Figure imgf000088_0001
A mixture of 3-bromo-4-chloro-1 -(phenylsulfonyl)-1 /-/-pyrazolo[3,4-d]pyrimidine (200 mg, 0.50 mmol), 3-amino-/V-methyl-4-[(1 -methylethyl)oxy]benzenesulfonamide (139 mg, 0.53 mmol), and /'-Pr2NEt (0.17 mL, 1 .0 mmol) in 1 ,4-dioxane (4 mL) was stirred at 80 °C in a sealed tube overnight. The reaction mixture was concentrated onto Celite® and then purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (85 mg, 29%) as an off-white solid. LCMS(ES) m/e 581 , 583(M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (d, J = 2.27 Hz, 1 H), 8.88 (s, 1 H), 8.76 (s, 1 H),
8.10 (dd, J = 1.26, 8.59 Hz, 2H), 7.81 (d, J = 7.58 Hz, 1 H), 7.65 - 7.73 (m, 2H), 7.53 (dd, J = 2.27, 8.59 Hz, 1 H), 7.34 - 7.44 (m, 2H), 4.90 (s, 1 H), 2.43 (d, J = 5.05 Hz, 3H), 1.38 (d, J = 6.06 Hz, 6H). c) 3-[(3-bromo-1 H-pyrazolo[3,4-c/]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide
Figure imgf000088_0002
A mixture of 3-{[3-bromo-1 -(phenylsulfonyl)-1 H-pyrazolo[3,4-d]pyrimidin-4- yl]amino}-/V-methyl-4-[(1 -methylethyl)oxy]benzenesulfonamide (85 mg, 0.15 mmol) and 6 N NaOH (0.12 mL, 0.73 mmol) in 1 :1 THF//'-PrOH (3 mL) was stirred at 100 °C under microwave conditions for 20 min. The mixture was neutralized with 1 N aq. HCI, concentrated onto Celite® and purified by flash column chromatography using 40-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (39 mg, 60%) as white solid. LCMS(ES) m/e 441 ,443(M, M+2); 1 H N MR (400 MHz, DMSO-d6) δ ppm 14.25 (br. s, 1 H), 9.26 (d, J = 2.27 Hz, 1 H), 8.81 (s, 1 H), 8.57 (s, 1 H), 7.51 (dd, J = 2.27, 8.59 Hz, 1 H), 7.33 - 7.43 (m, 2H), 4.88 - 4.99 (m, 1 H), 2.45 (d, J = 5.05 Hz, 3H), 1 .42 (d, J = 6.06 Hz, 6H).
EXAMPLE 21
A/-methyl-4-(methyloxy)-3-{[3-(1 -methyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4- yl]amino}benzenesulfonamide
Figure imgf000089_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (189 mg, 0.44 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (363 mg, 1 .74 mmol), PdCI2(dppf)«CH2CI2 (36 mg, 0.04 mmol) and 2 M aq. K2C03 (1 .09 mL, 2.18 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. 1 -Methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (182 mg) and Pd(f-Bu3P)2 (20 mg) were added to the mixture, which was heated at 100 °C for 30 min and then 150 °C for another 25 min under microwave conditions. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (33 mg, 18%) as an off-white solid. LCMS(ES) m/e 415 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 14.31 (s, 1 H), 9.30 (d, J = 2.27 Hz, 1 H), 8.62 (s, 1 H), 8.32 (s, 1 H), 7.83 (d, J = 1 .77 Hz, 1 H), 7.48 (dd, J = 2.27, 8.34 Hz, 1 H), 7.39 (d, J = 5.05 Hz, 1 H), 7.25 (d, J = 8.59 Hz, 1 H), 6.87 (d, J = 1.77 Hz, 1 H), 3.90 (s, 3H), 3.92 (s, 3H), 2.42 (d, J = 5.05 Hz, 3H). EXAMPLE 22
4-(dimethylamino)-3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]am
methylbenzenesulfonamide
Figure imgf000090_0001
A mixture of 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4- (dimethylamino)-/\/-methylbenzenesulfonamide (200 mg, 0.47 mmol), 3-furanylboronic acid (262 mg, 2.34 mmol), PdCI2(dppf)«CH2CI2 (38 mg, 0.05 mmol) and 2 M aq. K2C03 (1 .17 ml_, 2.35 mmol) in 1 ,4-dioxane (4 ml.) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (150 mg, 77%) as an off-white solid. LCMS(ES) m/e 414 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.96 (br. s, 1 H), 9.28 (s, 1 H), 8.92 (s, 1 H), 8.57 (s, 1 H), 8.27 (s, 1 H), 8.02 (s, 1 H), 7.45 (s, 3H), 6.92 (s, 1 H), 2.42 - 2.48 (m, 9H).
EXAMPLE 23
4-(dimethylamino)-/V-methyl-3-{[3-(5-methyl-2-furanyl)-1 /-/-pyrazolo[3,4-d]pyri
yl]amino}benzenesulfonamide
Figure imgf000090_0002
A mixture of 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-
(dimethylamino)-/V-methylbenzenesulfonamide (200 mg, 0.47 mmol), (5-methyl-2- furanyl)boronic acid (295 mg, 2.35 mmol), PdCI2(dppf)«CH2CI2 (38 mg, 0.05 mmol) and 2 M aq. K2C03 (1 .17 mL, 2.35 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (129 mg, 64%) as an off-white solid. LCMS (ES) m/e 428 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 14.00 (br. s, 1 H), 9.03 (s, 1 H), 8.64 (d, J = 2.27 Hz, 1 H), 8.45 (s, 1 H), 7.51 (dd, J = 2.15, 8.46 Hz, 1 H), 7.29 - 7.42 (m, 2H), 6.95 (d, J = 3.28 Hz, 1 H), 6.40 (dd, J = 1 .01 , 3.28 Hz, 1 H), 2.66 (s, 6H), 2.46 (d, J = 5.05 Hz, 3H), 2.42 (s, 3H).
EXAMPLE 24
4-(dimethylamino)-3-{[3-(2-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide
Figure imgf000091_0001
A mixture of 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4- (dimethylamino)-/V-methylbenzenesulfonamide (200 mg, 0.47 mmol), 2-furanylboronic acid (262 mg, 2.34 mmol), PdCI2(dppf CH2Cl2 (38 mg, 0.05 mmol) and 2 M aq. K2C03 (1 .17 ml_, 2.34 mmol) in 1 ,4-dioxane (4 ml.) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (149 mg, 77%) as an off-white solid. LCMS(ES) m/e 414 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 14.10 (br. s, 1 H), 9.72 (s, 1 H), 9.16 (d, J = 2.27 Hz, 1 H), 8.53 (s, 1 H), 7.92 (d, J = 1.01 Hz, 1 H), 7.47 - 7.53 (m, 1 H), 7.37 - 7.46 (m, 2H), 7.08 (d, J = 4.04 Hz, 1 H), 6.82 (dd, J = 1 .89, 3.41 Hz, 1 H), 2.66 - 2.74 (m, 6H), 2.46 (d, J = 5.05 Hz, 3H). EXAMPLE 25
4-(dimethylamino)-/V-methyl-3-{[3-(1-methyl-1 H-pyrazol-5-yl)-1 H-pyrazo
4-yl]amino}benzenesulfonamide
Figure imgf000092_0001
A mixture of 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4- (dimethylamino)-/\/-methylbenzenesulfonamide (200 mg, 0.47 mmol), 1 -methyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (586 mg, 2.81 mmol), Pd(f-Bu3P)2 (48 mg, 0.09 mmol) and 2 M aq. K2C03 (1.17 ml_, 2.34 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (79 mg, 39%) as light yellow solid. LCMS(ES) m/e 428 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm
14.27 (br. s, 1 H), 9.25 (d, J = 2.02 Hz, 1 H), 8.73 (s, 1 H), 8.61 (s, 1 H), 7.78 (d, J = 2.02 Hz, 1 H), 7.36 - 7.50 (m, 3H), 6.81 (d, J = 1.77 Hz, 1 H), 3.86 (s, 3H), 2.45 (d, J = 5.05 Hz, 3H), 2.42 (s, 6H). EXAMPLE 26
4-(dimethylamino)-/V-methyl-3-{[3-(1-methyl-1 /-/-pyrazol-4-yl)-1 /-/-pyrazolo[3,4-d]pyrimidin-
4-yl]amino}benzenesulfonamide
Figure imgf000092_0002
A mixture of 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4- (dimethylamino)-/V-methylbenzenesulfonamide (200 mg, 0.47 mmol), 1 -methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (586 mg, 2.81 mmol), Pd(f-Bu3P)2 (48 mg, 0.09 mmol) and 2 M aq. K2C03 (1.17 ml_, 2.34 mmol) in 1 ,4-dioxane (4 ml.) was heated at 150 °C under microwave conditions for 40 min.
The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with MeOH to afford the title compound (86 mg, 43%) as white solid. LCMS(ES) m/e 428 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.85 (br. s, 1 H), 9.18 - 9.26 (m, 1 H), 8.74 (s, 1 H), 8.54 (s, 1 H), 8.19 (s, 1 H), 7.85 (s, 1 H), 7.37 - 7.50 (m, 3H), 4.00 (s, 3H), 2.40 - 2.47 (m, 9H). EXAMPLE 27
A/-methyl-4-(methyloxy)-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4- yl]amino}benzenesulfonamide
Figure imgf000093_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (240 mg, 0.52 mmol), 1 -methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (653 mg, 3.1 mmol), Pd(f-Bu3P)2 (53 mg, 0.10 mmol) and 2 M aq. K2C03 (1 .3 ml_, 2.61 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and
concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with MeOH to afford the title compound (76 mg, 35%) as an off-white solid. LCMS(ES) m/e 415 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.86 (br. s, 1 H), 9.27 (d, J = 2.02 Hz, 1 H), 8.55 (s, 1 H), 8.28 (s, 1 H), 8.23 (s, 1 H), 7.90 (s, 1 H), 7.48 (dd, J = 2.27, 8.59 Hz, 1 H), 7.39 (d, J = 5.05 Hz, 1 H), 7.25 (d, J = 8.84 Hz, 1 H), 4.02 (s, 3H), 3.90 (s, 3H), 2.43 (d, J = 4.80 Hz, 3H). EXAMPLE 28
/V-methyl-4-[(1-methylethyl)oxy]-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide
Figure imgf000094_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide (200 mg, 0.45 mmol), 1 -methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (471 mg, 2.26 mmol), Pd(f-Bu3P)2 (46 mg, 0.09 mmol) and 2 M aq. K2C03 (1.1 ml_, 2.26 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (66 mg, 32%) as a white solid. LCMS(ES) m/e 443 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.86 (br. s, 1 H), 9.18 (d, J = 2.27 Hz, 1 H), 8.52 (s, 1 H), 8.24 (s, 1 H), 8.13 (s, 1 H), 7.89 (s, 1 H), 7.45 (dd, J = 2.27, 8.59 Hz, 1 H), 7.38 (d, J = 5.05 Hz, 1 H), 7.28 (d, J = 8.84 Hz, 1 H), 4.70 - 4.82 (m, 1 H), 3.97 (s, 3H), 2.45 (d, J = 5.05 Hz, 3H), 1 .15 (d, J = 6.06 Hz, 6H).
EXAMPLE 29
A/-methyl-4-[(1-methylethyl)oxy]-3-{[3-(1 -methyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide
Figure imgf000094_0002
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide (200 mg, 0.45 mmol), 1 -methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (471 mg, 2.26 mmol), Pd(f-Bu3P)2 (46 mg, 0.09 mmol) and 2 M aq. K2C03 (1.13 mL, 2.26 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (84 mg, 42%) as an off-white solid. LCMS(ES) m/e 443(M+H); 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.30 (br. s, 1 H), 9.13 (d, J = 2.27 Hz, 1 H), 8.58 (s, 1 H), 8.08 (s, 1 H), 7.72 (d, J = 2.02 Hz, 1 H), 7.46 (dd, J = 2.27, 8.84 Hz, 1 H), 7.37 (q, J = 5.05 Hz, 1 H), 7.28 (d, J = 8.84 Hz, 1 H), 6.81 (d, J = 1.77 Hz, 1 H), 4.78 (dt, J = 6.06, 12.13 Hz, 1 H), 3.95 (s, 3H), 2.44 (d, J = 5.05 Hz, 3H), 1 .21 (d, J = 6.06 Hz, 6H).
EXAMPLE 30
3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide
Figure imgf000095_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide (200 mg, 0.45 mmol), 2-furanylboronic acid (254 mg, 2.26 mmol), Pd(f-Bu3P)2 (46 mg, 0.09 mmol) and 2 M aq. K2C03 (1.13 mL, 2.26 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (67 mg, 34%) as a white solid. LCMS(ES) m/e 429(M+H); 1H NMR (400 MHz, DMSO-de) δ ppm 14.10 (br. s, 1 H), 9.24 (s, 1 H), 8.97 (d, J = 2.27 Hz, 1 H), 8.49 (s, 1 H), 7.97 (d, J = 1 .01 Hz, 1 H), 7.52 (dd, J = 2.40, 8.72 Hz, 1 H), 7.32 - 7.41 (m, 2H), 7.1 1 (d, J = 2.78 Hz, 1 H), 6.82 (dd, J = 1 .77, 3.28 Hz, 1 H), 4.77 - 4.91 (m, 1 H), 2.46 (d, J = 5.05 Hz, 3H), 1 .31 (d, J = 6.06 Hz, 6H). EXAMPLE 31
/V-methyl-4-[(1-methylethyl)oxy]-3-{[3-(5-methyl-2-furanyl)-1 H-pyrazolo[3,4-d]py
yl]amino}benzenesulfonamide
Figure imgf000096_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide (200 mg, 0.45 mmol), (5-methyl-2-furanyl)boronic acid (285 mg, 2.26 mmol), PdCI2(dppf)«CH2CI2 (37 mg, 0.04 mmol) and 2 M aq. K2C03 (1 .13 ml_, 2.26 mmol) in 1 ,4-dioxane (4 ml.) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (92 mg, 46%) as off white solid. LCMS(ES) m/e 443(M+H); 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.03 (br. s, 1 H), 8.82 - 8.93 (m, 2H), 8.46 (s, 1 H), 7.52 (dd, J = 2.27, 8.59 Hz, 1 H), 7.32 - 7.44 (m, 2H), 6.97 (d, J = 3.28 Hz, 1 H), 6.36 - 6.44 (m, 1 H), 4.71 (q, J = 6.06 Hz, 1 H), 2.48 (d, J = 4.80 Hz, 3H), 2.44 (s, 3H), 1 .21 (d, J = 6.06 Hz, 6H).
EXAMPLE 32
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide
Figure imgf000096_0002
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide (200 mg, 0.45 mmol), 3-furanylboronic acid (262 mg, 2.34 mmol), PdCI2(dppf)«CH2CI2 (37 mg, 0.04 mmol) and 2 M aq. K2C03 (1 .13 mL, 2.26 mmol) in 1 ,4-dioxane (4 ml.) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCIs) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (1 19 mg, 61 %) as an off-white solid. LCMS(ES) m/e 429(M+H); 1H NMR (400 MHz, DMSO-de) δ ppm 13.98 (br. s, 1 H), 9.25 (d, J = 2.27 Hz, 1 H), 8.55 (s, 1 H), 8.30 - 8.36 (m, 1 H), 8.22 (s, 1 H), 7.99 (t, J = 1.64 Hz, 1 H), 7.46 (dd, J = 2.27, 8.59 Hz, 1 H), 7.38 (q, J = 4.88 Hz, 1 H), 7.29 (d, J = 8.84 Hz, 1 H), 6.95 (s, 1 H), 4.73 - 4.88 (m, 1 H), 2.45 (d, J = 5.05 Hz, 3H), 1.21 (d, J = 6.06 Hz, 6H).
EXAMPLE 33
3-{[3-(3,6-dihydro-2/-/-pyran-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide
Figure imgf000097_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide (250 mg, 0.57 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (333 mg, 1 .59 mmol), PdCI2(dppf)«CH2CI2 (46 mg, 0.06 mmol) and 2 M aq. K2C03 (1.42 ml_, 2.83 mmol) in 1 ,4-dioxane (3.5 ml.) was heated at 150 °C under microwave conditions for 40 min. To the reaction mixture was added more 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (198 mg, 0.94 mmol) and PdCI2(dppf)«CH2CI2 (30 mg), then heated at 150 °C under microwave conditions for an additional 30 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with MeOH to afford the title compound (87 mg, 34%) as an off-white solid. LCMS(ES) m/e 445(MH+); 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.85 (br. s, 1 H), 9.06 (d, J = 2.27 Hz, 1 H), 8.49 (s, 1 H), 8.29 (s, 1 H), 7.48 (dd, J = 2.40, 8.72 Hz, 1 H), 7.38 (d, J = 5.05 Hz, 1 H), 7.33 (d, J = 8.84 Hz, 1 H), 6.32 (s, 1 H), 4.77 - 4.87 (m, 1 H), 4.32 (d, J =
2.53 Hz, 2H), 3.87 - 3.96 (m, 2H), 2.63 - 2.73 (m, 2H), 2.45 (d, J = 5.05 Hz, 3H), 1.37 (d, J = 6.06 Hz, 6H). EXAMPLE 34
/V-methyl-4-[(1 -methylethyl)oxy]-3-[(3-methyl-1 H-pyrazolo[3,4-d]pyrimid
yl)amino]benzenesulfonamide
Figure imgf000098_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide (250 mg, 0.56 mmol), trimethylboroxine (0.55 mL, 3.97 mmol), PdCI2(dppf)-CH2CI2 (46 mg, 0.06 mmol) and 2 M aq. K2C03 (1.41 mL, 2.83 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (1 17 mg, 55%) as an off-white solid. LCMS(ES) m/e 377(M+H); 1 H NMR (400 MHz, DMSO-d6) 5 ppm 13.27 - 13.52 (m, 1 H), 9.1 1 (d, J = 2.53 Hz, 1 H), 8.45 (s, 1 H), 8.28 (s, 1 H), 7.49 (dd, J = 2.27, 8.59 Hz, 1 H), 7.38 (q, J = 4.72 Hz, 1 H), 7.33 (d, J = 9.09 Hz, 1 H), 4.89 (dt, J = 5.97, 12.06 Hz, 1 H), 2.72 (s, 3H), 2.44 (d, J = 4.80 Hz, 3H), 1.39 (d, J = 5.81 Hz, 6H).
EXAMPLE 35
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(cyclohexyloxy)-/\/- methylbenzenesulfonamide
Figure imgf000098_0002
To a solution of cyclohexanol (0.699 mL, 6.98 mmol) in NMP (2 mL) was added NaH (60% dispersion in oil, 140 mg, 3.49 mmol). After stirring at rt for 1 h, 3-[(3-bromo- 1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/V-methylbe (200 mg,
0.50 mmol) was added. The mixture was stirred at rt for 20 min and then heated at 1 10 °C for 20 h. The mixture was cooled down to rt and purified with flash column column using 10-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (30 mg, 12%). LCMS(ES) m/e 481 ,483(M, M+2); 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.24 (s, 1 H), 9.21 (d, J = 2.27 Hz, 1 H), 8.77 (s, 1 H), 8.56 (s, 1 H), 7.50 (dd, J = 2.27, 8.59 Hz, 1 H), 7.34 - 7.44 (m, 2H), 4.58 - 4.69 (m, 1 H), 2.44 (d, J = 5.05 Hz, 3H), 2.08 (br. s, 2H), 1.78 (dt, J = 3.76, 12.95 Hz, 2H), 1 .49 - 1 .63 (m, 3H), 1 .34 - 1 .49 (m, 2H), 1.27 (d, J = 1 1.87 Hz, 1 H).
EXAMPLE 36
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(1- pyrrolidinyl)benzenesulfonamide
Figure imgf000099_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/\/- methylbenzenesulfonamide (180 mg, 0.44 mmol) and pyrrolidine (0.18 mL, 2.24 mmol) in EtOH (4 mL) was heated at 160 °C under microwave conditions for 60 min. To the reaction mixture was added more pyrrolidine, and the reaction was heated at 170 °C under microwave conditions for an additional 80 min. The organic layer was concentrated onto Celite® and purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2, followed by further purification by reverse phase HPLC using 10-50 CH3CN/water (0.1 % TFA in mobile phase). The resulting TFA salt was basified with 1 % NH4OH / 9% MeOH / 90% CHCI3 and concentrated down to dryness. The residue was triturated with water to afford the title compound (80 mg, 39%) as light pink solid. LCMS(ES) m/e 452,454(M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.03 (br. s, 1 H), 8.77 (s, 1 H), 8.31 (s, 1 H), 7.82 (d, J = 2.27 Hz, 1 H), 7.50 (dd, J = 2.27, 8.59 Hz, 1 H), 7.19 (d, J = 5.05 Hz, 1 H), 7.00 (d, J = 8.84 Hz, 1 H), 3.32 (s, 2H), 2.40 (d, J = 5.05 Hz, 3H), 1.78 - 1.90 (m, 4H). EXAMPLE 37
4-fluoro-/V-methyl-3-(9H-purin-6-ylamino)benzenesulfonamide
Figure imgf000100_0001
To a solution of 3-amino-4-fluoro-/V-methylbenzenesulfonamide (369 mg, 1.81 mmol) and 6-ch I oro-1 /-/-purine (240 mg, 1 .55 mmol) in DMF (10 ml.) in a microwave reaction tube was added AgOTf (771 mg, 3.0 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford an off-white solid which was triturated with CH2CI2 to afford the title compound (191 mg, 31 %) as a white solid. LCMS (ES) m/z 323 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (br. s, 3 H) 7.49 - 7.65 (m, 3 H) 8.18 (br. s, 1 H) 8.32 (br. s, 2 H) 9.63 (br. s, 1 H) 13.25 (br. s, 1 H).
EXAMPLE 38
A/-methyl-4-(4-morpholinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000100_0002
To a solution of 3-amino-/V-methyl-4-(4-morpholinyl)benzenesulfonamide (488 mg, 1.80 mmol) and 6-chloro-1 /-/-purine (232 mg, 1 .5 mmol) in 1 ,4-dioxane (10 mL) in a microwave reaction tube was added AgOTf (578 mg, 2.25 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled down to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 with 0.1 % ΝΗ3·Η20) to afford an off- white solid which was triturated with CH2CI2 to afford the title compound (361 mg, 59%) as a white solid. LCMS (ES) m/z 390 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (d, J=5.05 Hz, 3 H) 2.91 - 3.00 (m, 4 H) 3.82 (br. s, 4 H) 7.41 - 7.54 (m, 3 H) 8.36 (s, 1 H) 8.50 (s, 1 H) 8.95 (s, 1 H) 9.06 (s, 1 H) 13.36 (br. s, 1 H). EXAMPLE 39
/V-methyl-3-(1 H-purin-6-ylamino)-4-(1-pyrrolidinyl)benzenesulfonamid
Figure imgf000101_0001
A solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.310 mmol) in pyrrolidine (1 10 mg, 1.55 mmol) was sealed in a microwave reaction tube and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 with 0.1 % ΝΗ3·Η20) to afford an off-white solid which was triturated with CH2CI2 to afford the title compound (73 mg, 60%) as a white solid. LCMS (ES) m/z 374 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .73 - 1.83 (m, 4 H) 2.38 (d, J=5.05 Hz, 3 H) 3.28 - 3.35 (m, 4 H) 6.88 (d, J=8.84 Hz, 1 H) 7.1 1 (q, J=5.05 Hz, 1 H) 7.46 (dd, J=8.84, 2.27 Hz, 1 H) 7.55 (s, 1 H) 8.14 - 8.36 (m, 2 H) 9.22 (br. s, 1 H) 13.03 (br. s, 1 H).
EXAMPLE 40
methylamino)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamid
Figure imgf000101_0002
A heterogeneous mixture of AgOTf (0.70 g, 2.72 mmol), 2-chloropurine (0.35 g, 2.26 mmol) and 3-amino-4-(dimethylamino)-/V-methylbenzenesulfonamide (0.62 g, 2.72 mmol) in 1 ,4-dioxane (22 mL) was stirred at 100 °C in a sealed high pressure vessel for 18 h. A dark grey precipitate formed which contained most of the product. The reaction mixture was concentrated in vacuo, the solid residue dispersed into silica gel, and purified by flash column chromatography using 0-10% 10:1 :90 MeOH:NH4OH:EtOAc in EtOAc as eluent. The desired fractions were combined and concentrated in vacuo. The residue was dissolved in a small amount of CH2CI2 and MeOH and a white precipitate came out of solution upon concentration. This precipitate was collected to afford the title compound (350mg, 44.5%) as an off-white solid. LCMS (ES) m/e 348.0 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 2.46 (3 H, d, J=5.05 Hz) 2.75 (6 H, s) 7.33 - 7.42 (2 H, m) 7.43 - 7.50 (1 H, m) 8.32 (1 H, s) 8.46 (1 H, s) 8.83 (1 H, s) 8.89 (1 H, br. s) 13.30 (1 H, br. s).
EXAMPLE 41
A/-methyl-4-(methyloxy)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000102_0001
A heterogeneous mixture of AgOTf (0.70 g, 2.72 mmol), 2-chloropurine (0.35 g, 2.26 mmol) and 3-amino-/V-methyl-4-(methyloxy)benzenesulfonamide (0.60 g, 2.77 mmol) in 1 ,4-dioxane (1 1 ml.) was stirred at 100 °C in a sealed high pressure vessel for 18 h. The reaction mixture was filtered through a pad of Celite®, washing with MeOH. The filtrate was concentrated and purified by flash column chromatography, eluting with 10:1 :90 MeOH:NH4OH:CHCI3. The desired fractions were concentrated in vacuo to afford the title compound as a grey solid. The solid was redissolved in MeOH, filtered through an acrodisc (2 μΜ) and precipitated with CH2CI2. The resulting solid was collected to afford the title compound (326 mg, 43%) as an off-white solid. LCMS (ES) m/e 335.0 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (3 H, d, J=4.80 Hz) 4.01 (3 H, s) 7.23 - 7.42 (2 H, m) 7.51 (1 H, dd, J=8.59, 2.02 Hz) 8.32 (1 H, s) 8.39 - 8.62 (2 H, m) 8.95 (1 H, br. s) 13.33 (1 H, br. s).
EXAMPLE 42
A/-methyl-4-(1-piperidinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000102_0002
A solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (130 mg, 0.40 mmol) in piperidine (1 ml_, 10.12 mmol) was sealed in a microwave reactor and heated at 1 10 °C for 20 h. The mixture was cooled down to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford an off-white solid which was triturated with CH2CI2 to afford the title compound (60.1 mg, 37%) as a white solid. LCMS (ES) m/z 388 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .62 (br. s, 2 H) 1.77 (br. s, 4 H) 2.46 (d, J=4.80 Hz, 3 H) 2.90 (d, J=4.04 Hz, 4 H) 7.38 - 7.50 (m, 3 H) 8.36 (s, 1 H) 8.51 (s, 1 H) 8.89 (br. s, 1 H) 9.14 (br. s, 1 H) 13.36 (br. s, 1 H).
EXAMPLE 43
A/-methyl-4-(4-methyl-1-piperazinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000103_0001
A solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.310 mmol) in 1-methylpiperazine (31 1 mg, 3.10 mmol) was sealed in a microwave reaction tube and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford an off-white solid which was triturated with CH2CI2 to afford the title compound (91 mg, 69%) as a white solid. LCMS (ES) m/z 403 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (br, s, 2H), 2.47 (d, J = 40Hz, 3H) 2.78 (br. s, 4 H) 3.02 (br. s, 4 H) 7.41 - 7.51 (m, 4 H) 8.37 (s, 1 H) 8.49 (s, 1 H) 8.78 (br. s, 1 H) 9.07 (br. s, 1 H) 13.38 (br. s, 1 H).
EXAMPLE 44
A/-methyl-4-[(1 -methylethyl)oxy]-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000103_0002
To 2-propanol (3 ml_, 39.9 mmol) was added NaH (60% dispersion in oil, 62.0 mg, 1.55 mmol). After stirring at room temperature for 1 h, the mixture was treated with 4- fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol). The resulting mixture was sealed in a microwave reaction tube and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7%
MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford an off-white solid which was triturated with CH2CI2 to afford the title compound (41.1 mg, 35%) as a white solid. LCMS (ES) m/z 363 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .38 (d, J=6.06 Hz, 6 H) 2.45 (d, J=5.05 Hz, 3 H) 4.79 - 4.99 (m, 1 H) 7.27 - 7.40 (m, 2 H) 7.46 (dd, J=8.59, 2.27 Hz, 1 H) 8.29 - 8.41 (m, 1 H) 8.48 (d, J=6.82 Hz, 2 H) 9.05 (br. s, 1 H) 13.32 (br. s, 1 H).
EXAMPLE 45
A/-methyl-4-(1-piperazinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide trifluoroacetate
Figure imgf000104_0001
A solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in piperazine (267 mg, 3.10 mmol) was sealed in a microwave reaction tube and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford an off- white solid which was purified by reverse phase HPLC eluting with 5-30% CH3CN/water with 0.1 % TFA to afford the title compound (21 .4 mg, 18%) as a yellow solid. LCMS (ES) m/z 389 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (br. s, 3 H) 3.16 (br. s, 4 H) 3.29 (br. s, 4 H) 7.48 (d, J=4.55 Hz, 3 H) 8.41 (s, 1 H) 8.51 (s, 1 H) 8.82 (br. s, 1 H) 8.88 (br. s, 2 H) 8.97 (br. s, 1 H). EXAMPLE 46
4-{ethyl[2-(methyloxy)ethyl]amino}-/V-methyl-3-(1 H-purin-6-ylami e a) 4-{ethyl[2-(methyloxy)ethyl]amino}-/V-methyl-3-nitrobenzenesulfonamid
Figure imgf000105_0002
A solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (500 mg, 2.14 mmol) in A/-ethyl-2-(methyloxy)ethanamine (220 mg, 2.14 mmol) in a microwave reaction tube was sealed and heated at 1 10 °C for 18 h. The mixture was concentrated and purified by flash column chromatography (0-3% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford the title compound (615.9 mg, 91 %) as a yellow oil. LCMS (ES) m/z 318 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1 .09 (t, J=7.07 Hz, 3 H) 2.42 (br. s, 3 H) 3.19 (s, 3 H) 3.32 (d, J=7.33 Hz, 2 H) 3.36 - 3.40 (m, 2 H) 3.48 (t, J=5.43 Hz, 2 H) 7.45 (d, J=8.84 Hz, 2 H) 7.73 - 7.79 (m, 1 H) 8.03 (d, J=2.27 Hz, 1 H). b) 3-amino-4-{ethyl[2-(methyloxy)ethyl]amino}-/\/-methylbenzenesulfonamide
Figure imgf000105_0003
To a solution of 4-{ethyl[2-(methyloxy)ethyl]amino}-/V-methyl-3- nitrobenzenesulfonamide (600 mg, 1.89 mmol) in EtOH (10 mL) was added Pd/C (210 mg, 0.19 mmol). The mixture was put on a Parr shaker under 35 psi of H2 at rt. After 1 h, the mixture was filtered through a Celite® pad. The filtrate was concentrated to afford the title compound (429 mg, 79%) as a white solid. LCMS (ES) m/z 288 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 0.92 (t, J=7.07 Hz, 3 H) 2.39 (d, J=3.28 Hz, 3 H) 2.99 - 3.10 (m, 4 H) 3.22 (s, 3 H) 3.38 (br. s, 2 H) 5.27 (s, 2 H) 6.88 - 6.95 (m, 1 H) 7.06 - 7.1 1 (m, 2 H) 7.13 (d, J=3.79 Hz, 1 H). c) 4-{ethyl[2-(methyloxy)ethyl]amino}-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide To a solution of 3-amino-4-{ethyl[2-(methyloxy)ethyl]amino}-/\/- methylbenzenesulfonamide (205 mg, 0.71 mmol) and 6-ch I oro-1 /-/-purine (100 mg, 0.65 mmol) in 1 ,4-dioxane (5 ml.) in a microwave reaction tube was added AgOTf (216 mg, 0.84 mmol). The reaction vessel was sealed and heated at 100 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was triturated with CH2CI2 to afford the title compound (133 mg, 48%) as a light yellow solid. LCMS (ES) m/z 406 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (d, J=4.8 Hz, 3 H) 4.3 (s, 3 H) 7.36 (q, J=4.8 Hz, 3 H) 7.58 (s, 1 H) 7.64 (d, J=3.84 Hz, 1 H) 7.77 (d, J=8.34 Hz, 1 H) 8.02(s, 1 H) 8.51 (s, 1 H) 1 1.1 1 (br. s, 1 H) 12.87 (br. s, 1 H).
EXAMPLE 47
4-[ethyl(2-hydroxyethyl)amino]-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000106_0001
a) 4-[ethyl(2-hydroxyethyl)amino]-/V-methyl-3-nitrobenzenesulfonamide
Figure imgf000106_0002
A solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (500 mg, 2.14 mmol) in (2-ethylamino)ethanol (951 mg, 10.67 mmol) in a microwave reaction tube was sealed and heated at 1 10 °C for 18 h. The mixture was concentrated and purified by flash column chromatography (0-3% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford the title compound (620 mg, 96%) as a yellow oil. LCMS (ES) m/z 304 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1 .10 (t, J=7.07 Hz, 3 H) 2.42 (d, J=4.55 Hz, 3 H) 2.50 (br. s, 2 H) 3.23 - 3.30 (m, 2 H) 3.54 (d, J=5.56 Hz, 2 H) 4.73 (s, 1 H) 7.44 (d, J=9.09 Hz, 2 H) 7.73 (s, 1 H) 8.03 (d, J=2.27 Hz, 1 H). b) 3-amino-4-[ethyl(2-hydroxyethyl)amino -/V-methylbenzenesulfonamide
Figure imgf000107_0001
To a solution of 4-[ethyl(2-hydroxyethyl)amino]-/V-methyl-3- nitrobenzenesulfonamide (620 mg, 2.04 mmol) in EtOH (5 ml.) was added Pd/C (218 mg, 0.20 mmol). The mixture was put on a Parr shaker under 35 psi of H2 at rt. After 1 h, the mixture was filtered through a Celite® pad. The filtrate was concentrated to afford the title compound (502 mg, 90%) as a white solid. LCMS (ES) m/z 274 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=6.95 Hz, 3 H) 2.39 (d, J=4.80 Hz, 3 H) 2.94 (t, J=5.81 Hz, 2 H) 2.99 - 3.06 (m, 2 H) 3.45 (d, J=5.56 Hz, 2 H) 4.63 - 4.69 (m, 1 H) 5.39 (s, 2 H) 6.89 (dd, J=8.21 , 2.15 Hz, 1 H) 7.02 - 7.09 (m, 2 H) 7.1 1 (d, J=4.80 Hz, 1 H). c) 4-[ethyl(2-hydroxyethyl)amino]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide
To a solution of 3-amino-4-[ethyl(2-hydroxyethyl)amino]-/\/- methylbenzenesulfonamide (195 mg, 0.712 mmol) and 6-chloro-1 /-/-purine (100 mg, 0.647 mmol) in 1 ,4-dioxane (5 ml.) in a microwave reaction tube was added AgOTf (216 mg, 0.84 mmol). The reaction vessel was sealed and heated at 100 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford the title compound (94 mg, 35%) as a yellow solid. LCMS (ES) m/z 392 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (t, J=6.95 Hz, 3 H) 2.47 (d, J=4.55 Hz, 2 H) 3.06 - 3.13 (m, 3 H) 3.17 (br. s, 2 H) 3.45 (t, J=6.06 Hz, 2 H) 4.69 (br. s, 1 H) 7.36 - 7.60 (m, 3 H) 8.32 (s, 1 H) 8.41 - 8.56 (m, 1 H) 9.07 (br. s, 1 H) 9.29 (br. s, 1 H) 13.29 (br. s, 1 H). EXAMPLE 48
4-[(cyclohexylmethyl)oxy]-/V-methyl-3-(1 H-purin-6-ylam
Figure imgf000108_0001
To cyclohexylmethanol (354 mg, 3.10 mmol) was added NaH (60% dispersion in oil, 62 mg, 1 .55 mmol). After stirring at rt for 0.5 h, the mixture was transferred into a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 ml.) in a microwave reaction tube. The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which triturated with CH2CI2 to afford the title compound (58 mg, 43%) as a white solid. LCMS (ES) m/z 417 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 - 1.20 (m, 3 H) 1.25 (d, J=12.13 Hz, 2 H) 1.70 (d, J=12.38 Hz, 3 H) 1.79 (d, J=10.36 Hz, 3 H) 2.44 (d, J=5.05 Hz, 3 H) 4.01 (d, J=5.56 Hz, 2 H) 7.28 (d, J=8.59 Hz, 1 H) 7.35 (q, J=4.97 Hz, 1 H) 7.47 (dd, J=8.59, 2.27 Hz, 1 H) 8.32 (s, 1 H) 8.45 (s, 1 H) 8.58 (br. s, 1 H) 8.92 (br. s, 1 H) 13.31 (br. s, 1 H).
EXAMPLE 49
4-(cyclopentyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide di- trifluoroacetate
Figure imgf000108_0002
To cyclopentanol (0.31 1 mL, 3.10 mmol) was added NaH (60% dispersion in oil, 62 mg, 1.55 mmol). After stirring at rt for 0.5 h, the mixture was transferred into a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 mL) in a microwave reaction tube. The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was purified by reverse phase HPLC eluting with 10-50% CH3CN/water with 0.1 % TFA to afford the title compound (12.1 mg, 10%) as a white solid. LCMS (ES) m/z 389 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63 (br. s, 2 H) 1.72 (br. s, 2 H) 1.82 (br. s, 2 H) 1 .98 (br. s, 2 H) 2.45 (s, 3 H) 5.08 (br. s, 1 H) 7.28 (s, 1 H) 7.36 (br. s, 1 H) 7.48 (br. s, 1 H) 8.33 (s, 1 H) 8.46 (s, 1 H) 8.52 (br. s, 1 H) 8.96 (br. s, 1 H) 13.34 (br. s, 1 H).
EXAMPLE 50
4-[(2-cyclohexylethyl)oxy]-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000109_0001
To cyclohexylethanol (0.40 mL, 3.10 mmol) was added NaH (60% dispersion in oil, 62 mg, 1.55 mmol). After stirring at rt for 0.5 h, the mixture was transferred into the solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 mL) in a microwave reaction tube. The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was purified by reverse phase HPLC eluting with 10-50% CH3CN/water with 0.1 % TFA. The collected fractions were concentrated and made basic to a pH ~8 with
ΝΗ3·Η20. A white solid was precipitated. The solid was collected by filtration, triturated with water, and dried in vacuo overnight to afford the title compound (19 mg, 14%) as a white solid. LCMS (ES) m/z 431 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (d, J=12.13 Hz, 2 H) 1.14 (d, J=5.56 Hz, 3 H) 1 .60 - 1 .74 (m, 7 H) 2.44 (d, J=5.05 Hz, 3 H) 3.17 (d, J=5.31 Hz, 1 H) 4.22 (t, J=6.44 Hz, 2 H) 7.30 (d, J=8.59 Hz, 2 H) 7.36 - 7.43 (m, 1 H) 7.48 (dd, J=8.59, 2.27 Hz, 1 H) 8.31 (br. s, 1 H) 8.44 (s, 1 H) 8.58 (br. s, 1 H) 8.89 (br. s, 1 H). EXAMPLE 51
4-(cyclohexyloxy)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide
Figure imgf000110_0001
To cyclohexanol (0.31 mL, 3.10 mmol) was added NaH (60% dispersion in oil, 62 mg, 1 .55 mmol). After stirring at rt for 0.5 h, the mixture was transferred into a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 mL) in a microwave reaction tube. The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column
chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was purified by reverse phase HPLC eluting with 10-50% CH3CN/water with 0.1 % TFA. The collected fractions were concentrated and made basic to a pH ~8 with
ΝΗ3·Η20. A white solid precipitated. The solid was collected by filtration, triturated with water, and dried in vacuo overnight to afford the title compound (21 mg, 16%) as a white solid. LCMS (ES) m/z 403 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .46 (br. s, 4 H) 1.61 (br. s, 2 H)1 .73 (br. s, 2 H) 1 .94 (br. s, 2 H) 2.45 (d, J=5.05 Hz, 3 H) 4.69 (br. s, 1 H) 7.32 - 7.40 (m, 2 H) 7.43 - 7.50 (m, 1 H) 8.33 (br. s, 1 H) 8.48 (s, 1 H) 8.54 (br. s, 1 H) 9.08 (br. s, 1 H) 13.35 (br. s, 1 H).
EXAMPLE 52
A/-methyl-3-(1 /-/-purin-6-ylamino)-4-{[2-(1-pyrrolidinyl)ethyl]oxy} benzenesulfonamide
Figure imgf000110_0002
To 2-(1 -pyrrolidinyl)ethanol (2 mL, 17.1 mmol) in a microwave reaction tube was added NaH (60% dispersion in oil, 30 mg, 1.24 mmol). After stirring at rt for 0.5 h, 4- fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (80 mg, 0.25 mmol) was added. The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by reverse phase HPLC eluting with 7-40% CH3CN/water with 0.1 % TFA. The collected fractions were concentrated and made basic to a pH ~8 with ΝΗ3·Η20. A white solid precipitated out. The solid was collected by filtration, triturated with water, and dried in vacuo overnight to afford the title compound (67.4 mg, 62%) as a white solid. LCMS (ES) m/z 418 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .65 (br. s, 4 H) 2.46 (s, 3 H) 2.56 (br. s, 4 H) 2.86 (br. s, 2 H) 4.31 (br. s, 2 H) 7.33 (s, 2 H) 7.47 (s, 1 H) 8.32 (s, 1 H) 8.45 (s, 1 H) 8.68 (br. s, 1 H) 8.97 (br. s, 1 H) 13.18 (br. s, 1 H).
EXAMPLE 53
4-[3-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide
Figure imgf000111_0001
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (80 mg, 0.25 mmol) in NMP (1 ml.) in a microwave reaction tube was added
3-piperidinylmethanol (29 mg, 0.25 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was triturated with CH2CI2 to afford the title compound (44 mg, 40%) as a light yellow solid. LCMS (ES) m/z 418 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (br. s, 1 H) 1.81 (br. s, 3 H) 1 .94 (br. s, 1 H) 2.46 (br. s, 3 H) 2.64 (br. s, 4H) 2.98(br. s, 1 H) 3.13 (d, J=10.1 1 Hz, 1 H) 4.53 (d, J=9.85 Hz, 1 H) 7.36 - 7.52 (m, 3 H) 8.36 (s, 1 H) 8.51 (s, 1 H) 8.94 (br. s, 1 H) 9.15 (br. s, 1 H) 13.36 (d, J=3.28 Hz, 1 H). EXAMPLE 54
A/-methyl-4-{[2-(1 -piperidinyl)ethyl]oxy}-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000111_0002
To 2-(1 -piperidinyl)ethanol (32 mg, 0.25 mmol) was added NaH (60% dispersion in oil, 50 mg, 1 .241 mmol). After stirring at rt for 0.5 h, the mixture was transferred into a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (80 mg, 0.25 mmol) in NMP (1 ml.) in a microwave reaction tube. The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was further purified by reverse phase HPLC eluting with 10-50% CH3CN/water with 0.1 % TFA. The collected fractions were concentrated and made basic to a pH ~8 with ΝΗ3·Η20. A white solid precipitated out. The solid was collected by filtration, triturated with water, and dried in vacuo overnight to afford the title compound (23.4 mg, 21 %) as a white solid. LCMS (ES) m/z 432 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .32 (br. s, 2 H) 1.39 - 1.53 (m, 5 H) 2.44 (s, 3 H) 2.45 (s, 3 H) 2.72 (br. s, 2 H) 4.30 (t, J=5.56 Hz, 2 H) 7.29 - 7.41 (m, 2 H) 7.47 (dd, J=8.59, 2.27 Hz, 1 H) 8.32 (s, 1 H) 8.45 (s, 1 H) 8.62 (br. s, 1 H) 8.95 (br. s, 1 H) 13.31 (br. s, 1 H).
EXAMPLE 55
4-[4-(2-hydroxyethyl)-1-piperidinyl]-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000112_0001
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (120 mg, 0.37 mmol) in NMP (2 ml.) in a microwave reaction tube was added 2-(4- piperidinyl)ethanol (48 mg, 0.37 mmol). The tube was sealed and the mixture was heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by reverse phase HPLC eluting with 5-30% CH3CN/water with 0.1 % TFA. The desired fractions were dissolved in 1 :1 water/MeOH (1 mL) and made basic to a pH ~8 with ΝΗ3·Η20. A white solid precipitated out. The precipitate was filtered, washed with water and CH2CI2, and then dried in vacuo for 20 h to afford the title compound (57 mg, 34%) as a white solid. LCMS (ES) m/z 432 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 - 1.51 (m, 3 H) 1.57 (br. s, 1 H) 1.85 (br. s, 2 H) 2.46 (d, J=5.05 Hz, 3 H) 2.73 (t, J=1 1 .75 Hz, 2 H) 3.08 (d, J=^ ^ .^ 2 Hz, 2 H) 3.49 - 3.53 (m, 2 H) 4.37 - 4.53 (m, 1 H) 7.35 - 7.60 (m, 3 H) 8.36 (s, 1 H) 8.50 (s, 1 H) 8.82 (s, 1 H) 9.12 (s, 1 H) 13.35 (br. s, 1 H).
EXAMPLE 56
/V-methyl-4-{[2-(4-piperidinyl)ethyl]oxy}-3-(1 H-purin-6-ylamino)benzenes
Figure imgf000113_0001
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (120 mg, 0.37 mmol) in NMP (2 mL) in a microwave reaction tube was added 2-(4- piperidinyl)ethanol (48 mg, 0.37 mmol). The tube was sealed and the mixture was heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by reverse phase HPLC eluting with 5-30% CH3CN/water with 0.1 % TFA. The desired fractions were dissolved in 1 mL water/MeOH (1 :1 ) and made basic to a pH ~8 with ΝΗ3·Η20. A white solid precipitated out. The precipitate was filtered, washed with water and CH2CI2, and then dried in vacuo for 20 h to afford the title compound (7 mg, 4%) as a white solid. LCMS (ES) m/z 432 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (br. s, 3 H) 1.40 (d, J=6.32 Hz, 2 H) 1 .74 (br. s, 3 H) 2.42 (d, J=5.05 Hz, 3 H) 2.67 (dd, J=3.54, 2.02 Hz, 1 H) 2.84 (br. s, 1 H) 3.32 (m, 2H) 3.73 (br. s, 1 H) 4.41 (t, J=5.05 Hz, 2 H) 7.40 - 7.51 (m, 3 H) 7.61 (d, J=2.02 Hz, 1 H) 8.17 (d, J=8.34 Hz, 1 H) 8.53 (s, 1 H) 8.81 (s, 1 H).
EXAMPLE 57
4-[ethyl(methyl)amino]-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000113_0002
A heterogeneous mixture of 3-amino-4-[ethyl(methyl)amino]-/\/- methylbenzenesulfonamide (0.3 g, 1.23 mmol), 6-chloropurine (0.19 g, 1 .23 mmol), and AgOTf (0.38 g, 1 .48 mmol) in 1 ,4-dioxane (12 mL) was stirred at 100 °C in a sealed high pressure vessel for 18 h. A dark grey precipitate formed which contained most of the product. The reaction mixture was concentrated in vacuo, the solid residue dispersed into silica gel, and purified by flash column chromatography using 0-60% 10:1 :90
MeOH:NH4OH:EtOAc in EtOAc as eluent. The desired fractions were combined and concentrated in vacuo. The residue was dissolved in a small amount of CH2CI2 and MeOH and a white precipitate came out of solution upon concentration. This precipitate was collected, washing with CH2CI2 to afford the title compound (108 mg, 24%) as a yellow solid. LCMS (ES) m/e 362.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .12 (3 H, t, J=6.95 Hz) 2.47 (3 H, d, J=5.05 Hz) 2.75 (3 H, s) 2.95 (2 H, q, J=7.07 Hz) 7.33 - 7.54 (3 H, m) 8.33 (1 H, s) 8.49 (1 H, s) 8.93 (1 H, s) 9.06 (1 H, br. s) 13.35 (1 H, br. s).
EXAMPLE 58
4-[4-(hydroxymethyl)-1 -piperidinyl]-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000114_0001
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (120 mg, 0.37 mmol) in NMP (1 ml.) in a microwave reaction tube was added
4-piperidinylmethanol (429 mg, 3.72 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by reverse phase HPLC eluting with 5-30% CH3CN/water. The collected fractions were concentrated and made basic with ΝΗ3·Η20 to pH -13. A precipitate formed. The precipitate was filtered, washed with water and CH2CI2, and the dried in vacuo to afford the title compound (44 mg, 27%) as an off-white solid. LCMS (ES) m/z 418 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.38 - 1.49 (m, 2 H) 1 .56 (d, J=10.4 Hz, 1 H) 1.84 (d, =^ A Hz, 2 H) 2.47 (d, J=4.8 Hz, 3 H) 2.49 (br. s, 1 H) 2.52 (br. s, 1 H) 2.72 - 2.79 (m, 2 H) 3.1 1 (d, J=1 1 .4 Hz, 2 H) 4.58 (br. s, 1 H) 7.39 - 7.48 (m, 3 H) 8.36 (s, 1 H) 8.50 (s, 1 H) 8.80 (br. s, 1 H) 9.13 (br. s, 1 H) 13.36 (br. s, 1 H). EXAMPLE 59
4-[2-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 H-purin-6-ylamin
di-trifluoroacetate
Figure imgf000115_0001
a) 4-[2-(hydroxymethyl)-1-piperidinyl]-/V-meth l-3-nitrobenzenesulfonamide
Figure imgf000115_0002
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (600 mg, 2.56 mmol) in 1 ,4-dioxane (10 mL) was added 2-piperidinylmethanol (590 mg, 5.12 mmol). The mixture was heated at 100 °C for 20 h. The mixture was cooled to rt and passed through a silica gel pad with 0.5% MeOH/CH2Cl2 to afford the title compound (515 mg, 61 %) as a yellow oil. LCMS (ES) m/z 330 (M+H)+. b) 3-amino-4-[2-(hydroxymethyl)-1 -piperidinyl]-/\/-methylbenzenesulfonamide
Figure imgf000115_0003
To a solution of 4-[2-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3- nitrobenzenesulfonamide (500 mg, 1.52 mmol) in EtOH (10 mL) was added Pd/C (27 mg, 0.15 mmol). The solution was put on a Parr shaker under 35 psi of H2 at rt for 40 min. The mixture was filtered through a Celite® pad, concentrated, and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (387 mg, 85%) as a white foamy solid. LCMS (ES) m/z 300 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 - 1.50 (m, 2 H) 1.58 - 1 .64 (m, 2 H) 1 .73 (dd, J=9.47, 4.93 Hz, 1 H) 1.87 - 1.96 (m, 1 H) 2.37 - 2.41 (m, 3 H) 2.52 - 2.59 (m, 1 H) 2.94 (ddd, J=1 1.49, 4.67, 4.29 Hz, 1 H) 3.00 - 3.05 (m, 1 H) 3.14 - 3.21 (m, 1 H) 3.25 - 3.33 (m, 1 H) 4.38 - 4.41 (m, 1 H) 5.26 (s, 2 H) 6.91 (dd, J=8.08, 2.27 Hz, 1 H) 7.06 (d, J=2.27 Hz, 1 H) 7.12 - 7.17 (m, 2H). c) 4-[2-(hydroxymethyl)-1-piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide di-trifluoroacetate
To a solution of 3-amino-4-[2-(hydroxymethyl)-1 -piperidinyl]-/\/- methylbenzenesulfonamide (150 mg, 0.50 mmol) and 6-ch I oro-1 /-/-purine (85 mg, 0.55 mmol) in 1 ,4-dioxane (5 mL) in a microwave reaction tube was added AgOTf (386 mg, 1.50 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid. The solid was further purified by reverse phase HPLC eluting with 5-30% CH3CN/water with 0.1 % TFA to afford the title compound (19.7 mg, 9%) as a yellow solid. LCMS (ES) m/z 418 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1 .69 (m, 5 H) 1.85 (br. s, 1 H) 1.98 (br. s, 1 H) 2.74 (d, J=7.83 Hz, 3 H) 2.93 (br. s, 1 H) 3.06 (br. s, 1 H) 3.15 - 3.32 (m, 4 H) 7.40 - 7.51 (m, 2 H) 7.54 (d, J=8.34 Hz, 1 H) 8.37 (s, 1 H) 8.51 (s, 1 H) 9.13 (br. s, 1 H) 9.51 (br. s, 1 H).
EXAMPLE 60
A/-methyl-3-(1 /-/-purin-6-ylamino)-4-[4-(trifluoromethyl)-1 -piperidinyl]benzenesulfonamide
Figure imgf000116_0001
a) A/-methyl-3-nitro-4-[4-(trifluoromethyl)-1-piperidinyl]benzenesulfonamide
Figure imgf000116_0002
To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (320 mg, 1.37 mmol) in 1 ,4-dioxane (5 mL) in a microwave reaction tube was added 4-(trifluoromethyl)piperidine (209 mg, 1.37 mmol). The mixture was heated at 100 °C for 20 h and purified by flash column chromatography (10-70% EtOAc/hexanes) to afford the title compound (330 mg, 68%) as a yellow oil. LCMS (ES) m/z 368 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (td, J=12.19, 3.66 Hz, 2 H) 1 .90 (d, J=12.38 Hz, 2 H) 2.42 (br. s, 3 H) 2.60 (br. s, 2 H) 3.04 (t, J=12.51 Hz, 2 H) 7.46 (d, J=8.84 Hz, 1 H) 7.52 (br. s, 1 H) 7.83 (dd, J=8.84, 2.27 Hz, 1 H) 8.14 (d, J=2.27 Hz, 1 H). b) 3-amino-/V-methyl-4-[4-(trifluoromethyl)-1 -piperidinyl]benzenesulfonam
Figure imgf000117_0001
To a solution of A/-methyl-3-nitro-4-[4-(trifluoromethyl)-1- piperidinyl]benzenesulfonamide (330 mg, 0.90 mmol) in EtOH (5 mL) was added Pd/C (16 mg, 0.09 mmol). The solution was put on a Parr shaker under 35 psi of H2 at rt for 40 min. The mixture was filtered through a Celite® pad, concentrated, and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (267 mg, 88%) as an off-white solid. LCMS (ES) m/z 338 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.76 (br. s, 2 H) 1.86 (br. s, 2 H) 2.38 (d, J=5.05 Hz, 5 H) 3.28 (br. s, 3 H) 5.19 (br. s, 2 H) 6.96 (br. s, 2H) 7.08 (br. s, 2 H). c) A/-methyl-3-(1 /-/-purin-6-ylamino)-4-[4-(trifluoromethyl)-1- piperidinyl]benzenesulfonamide
To a solution of 3-amino-/V-methyl-4-[4-(trifluoromethyl)-1- piperidinyl]benzenesulfonamide (200 mg, 0.59 mmol) and 6-chloro-1 /-/-purine (92 mg, 0.59 mmol) in 1 ,4-dioxane (5 mL) in a microwave reaction tube was added AcOH (0.17 mL, 2.96 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid. The solid was purified by reverse phase HPLC eluting with 7-35% CH3CN/water with 0.1 % TFA. The desired fractions were pooled, concentrated, and made basic with ΝΗ3·Η20 to pH -12. A precipitate formed. The precipitate was triturated with water and CH2CI2 to afford the title compound (39 mg, 14%) as an off-white solid. LCMS (ES) m/z 456 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.70 - 1.82 (m, 2 H) 1.97 (d, J=1 1 .87 Hz, 2 H) 2.46 (d, J=4.80 Hz, 3 H) 2.81 (t, J=1 1 .49 Hz, 2 H) 4.07 - 4.21 (m, 3 H) 7.37 - 7.50 (m, 3 H) 8.37 (s, 1 H) 8.47 - 8.53 (m, 1 H) 8.79 (br. s, 1 H) 9.05 (br. s, 1 H) 13.34 (br. s, 1 H). EXAMPLE 61
/V-methyl-3-(1 H-purin-6-ylamino)-4-[3-(trifluoromethyl)-1 -piperidiny
Figure imgf000118_0001
a) A/-methyl-3-nitro-4-[3-(trifluoromethyl)-1-piperidinyl]benzenesulfonamide
Figure imgf000118_0002
To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (320 mg, 1.37 mmol) in 1 ,4-dioxane (5 mL) was added 3-(trifluoromethyl)piperidine (251 mg, 1 .64 mmol). The mixture was heated at 100 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (381 mg, 76%) as a brown oil. LCMS (ES) m/z 368 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (br. s, 1 H) 1 .65 (br. s, 1 H) 1.80 (br. s, 1 H) 1.98-2.02 (m, 2H), 2.43 (s, 3H) 2.71 br. s, 1 H) 2.92 - 3.05 (m, 2H) 3.32 (m, 1 H) 7.48 (s, 1 H) 7.56 (br. s, 1 H) 7.82 - 7.90 (m, 1 H) 8.16 (s, 1 H). b) 3-amino-/V-methyl-4-[3-(trifluoromethyl)-1 -piperidinyl]benzenesulfonamide
Figure imgf000118_0003
To a solution of A/-methyl-3-nitro-4-[3-(trifluoromethyl)-1- piperidinyl]benzenesulfonamide (380 mg, 1.03 mmol) in EtOH (5 mL) was added Pd/C (18 mg, 0.10 mmol). The solution was put on a Parr shaker under 35 psi of H2 at rt for 40 min. The mixture was filtered through a Celite® pad, concentrated, and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (300 mg, 86%) as a yellow oil. LCMS (ES) m/z 338 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .37 (br. s, 1 H) 1 .73 (br. s, 1 H) 1.81 (br. s, 1 H) 1.99 (br. s, 1 H) 2.37 (s, 3 H) 2.44 (br. s, 1 H) 2.85 (br. s, 1 H) 3.05 (br. s, 1 H) 3.29 (br. s, 1 H) 5.24 (br. s, 2 H) 6.94 (s, 1 H) 7.03 (s, 1 H) 7.09 (s, 1 1-1) 7.15 (br. s, 1 H). c) /V-methyl-3-(1 H-purin-6-ylamino)-4-[3-(trifluoromethyl)-1- piperidinyljbenzenesulfonamide
To a solution of 3-amino-/V-methyl-4-[4-(trifluoromethyl)-1- piperidinyl]benzenesulfonamide (200 mg, 0.59 mmol) and 6-chloro-1 /-/-purine (92 mg, 0.59 mmol) in 1 ,4-dioxane (5 ml.) in a microwave reaction tube was added AcOH (0.17 ml_, 2.96 mmol). The reaction vessel was sealed and heated at 100 °C for 20 h. The mixture was cooled to rt and purified by reverse phase HPLC eluting with 7-35% CH3CN/water with 0.1 % TFA. The desired fractions were pooled, concentrated, and made basic with ΝΗ3·Η20 to pH -12. A precipitate formed. The precipitate was triturated with water and CH2CI2 to afford the title compound (92 mg, 34%) as a white yellow solid. LCMS (ES) m/z 456 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .42 - 1.56 (m, 1 H) 1 .80 (d, J=12.13 Hz, 1 H) 1.91 (d, J=12.88 Hz, 1 H) 2.04 (br. s, 1 H) 2.47 (d, J=5.05 Hz, 3 H) 2.67 - 2.76 (m, 2 H) 2.88 (t, J=10.86 Hz, 1 H) 3.08 (d, J=^ ^ .^2 Hz, 1 H) 3.23 - 3.30 (m, 1 H) 7.46 (s, 3 H) 8.36 (s, 1 H) 8.49 (s, 1 H) 8.82 (s, 1 H) 9.02 (s, 1 H) 13.36 (br. s, 1 H).
EXAMPLE 62
4-[3-(hydroxymethyl)-1-pyrrolidinyl]-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000119_0001
A mixture of 4-fluoro-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide (0.3 g,
0.931 mmol) and 3-pyrrolidinylmethanol (0.282 g, 2.79 mmol) in NMP (2.327 mL) was stirred at 1 10 °C in a sealed high pressure vessel for 18 h. The reaction mixture became homogeneous and turned a dark brown. The reaction mixture was dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-10% of a 9:1 :0.1 solution of CHCI3:MeOH:NH4OH. The desired fractions were combined and concentrated in vacuo. The residue was taken into a small amount of MeOH and a 1 :1 EtOAc:hexanes mixture was titrated in to crash out the title compound as an off-white solid. This precipitate was collected and dried in vacuo to afford the title compound (0.22 g, 58.6%) as a pale yellow solid. LCMS (ES) m/e 404.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (1 H, dd, J=1 1 .87, 7.07 Hz) 1 .85 (1 H, d, J=6.32 Hz) 2.18 - 2.31 (1 H, m) 2.39 (3 H, d, J=4.80 Hz) 3.09 - 3.20 (1 H, m) 3.23 - 3.46 (5 H, m) 4.64 (1 H, t, J=4.93 Hz) 6.87 (1 H, d, J=8.59 Hz) 7.06 - 7.19 (1 H, m) 7.46 (1 H, dd, J=8.72, 1 .89 Hz) 7.58 (1 H, s) 8.19 (2
H, d, J=7.07 Hz) 9.24 (1 H, s) 13.08 (1 H, br. s); 1H NMR (400 MHz, MeOH-d4) δ ppm
I .63 - 1.77 (1 H, m) 1.97 - 2.09 (1 H, m) 2.35 - 2.50 (1 H, m) 2.56 (3 H, s) 3.26 (1 H, dd, J=9.60, 6.32 Hz) 3.39 - 3.59 (5 H, m) 7.05 (1 H, d, J=8.84 Hz) 7.61 (1 H, dd, J=8.84, 2.27 Hz) 7.93 (1 H, d, J=2.02 Hz) 8.19 (1 H, s) 8.28 (1 H, s).
EXAMPLE 63
4-[4-(dimethylamino)-1-piperidinyl]-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000120_0001
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 mL) in a microwave reaction tube was added N,N- dimethyl-4-piperidinamine (40 mg, 0.31 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was triturated with CH2CI2 to afford the title compound (42 mg, 30%) as a light yellow solid. LCMS (ES) m/z 431 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .66 (d, J=1 1 .62 Hz, 2 H) 1.91 (br. s, 2 H) 2.20 - 2.28 (m, 7 H) 2.46 (d, J=4.80 Hz, 3 H) 2.74 (t, J=1 1 .62 Hz, 2 H) 3.10 - 3.20 (m, 3 H) 7.37 - 7.49 (m, 3 H) 8.35 (s, 1 H) 8.49 (s, 1 H) 8.85 (s, 1 H) 9.06 (br. s, 1 H). EXAMPLE 64
4-(3-hydroxy-1-pyrrolidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfon
Figure imgf000121_0001
A mixture of 4-fluoro-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide (0.3 g, 0.931 mmol) and 3-pyrrolidinol (0.243 g, 2.79 mmol) in NMP (2.327 mL) was stirred at 120 °C in a sealed high pressure vessel for 18 h. The reaction mixture became homogeneous and turned a dark brown. The reaction mixture was dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-100% of a 90:9:1 solution of
CHCl3:MeOH:NH4OH in CHCI3. The desired fractions were combined and concentrated in vacuo. The residue was taken into a small amount of MeOH and a 1 :1 EtOAc:hexanes mixture was added to crash out the title compound as an off-white solid. This precipitate was collected and dried in vacuo to afford the title compound (148 mg, 40.8%) as an off- white solid. LCMS (ES) m/e 390.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 - 1.92 (2 H, m) 2.39 (3 H, d, J=5.05 Hz) 3.16 (1 H, d, J=10.1 1 Hz) 3.38 (1 H, m) 3.40 - 3.64 (2 H, m) 4.16 - 4.35 (1 H, m) 4.81 - 5.02 (1 H, m) 6.85 (1 H, d, J=8.84 Hz) 7.10 (1 H, q, J=4.80 Hz) 7.37 - 7.61 (2 H, m) 8.19 (2 H, s) 9.25 (1 H, br. s) 13.03 (1 H, br. s).
EXAMPLE 65
4-(4-cyano-1 -piperidinyl)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000121_0002
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 mL) in a microwave reaction tube was added
4-piperidinecarbonitrile (34 mg, 0.31 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column
chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was triturated with CH2CI2 to afford the title compound (60 mg, 47%) as a light yellow solid. LCMS (ES) m/z 413 (M+H)+; 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .91 - 2.01 (m, 2 H) 2.07 - 2.15 (m, 2 H) 2.47 (d, J=4.80 Hz, 3 H) 2.85 - 2.95 (m, 2 H) 3.01 - 3.09 (m, 2 H) 3.15 (br. s, 1 H) 7.39 - 7.49 (m, 3 H) 8.38 (s, 1 H) 8.50 (s, 1 H) 8.80 (s, 1 H) 9.05 (br. s, 1 H) 13.27 (br. s, 1 H).
EXAMPLE 66
A/-methyl-4-{2-[2-(methyloxy)ethyl]-1-piperidinyl}-3-(1 H-purin-6- ylamino)benzenesulfonamide
Figure imgf000122_0001
a) A/-methyl-4-{2-[2-(methyloxy)ethyl]- -piperidinyl}-3-nitrobenzenesulfonamide
Figure imgf000122_0002
To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (320 mg, 1.37 mmol) in 1 ,4-dioxane (5 ml.) in a microwave reaction tube was added 2-[2- (methyloxy)ethyl]piperidine (215 mg, 1.50 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (288 mg, 59%) as a brown oil. LCMS (ES) m/z 358 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .57 (br. s, 2 H) 1 .65 (br. s, 3 H) 1.78 (br. s, 1 H) 1.98 (s, 1 H) 2.39 (s, 3 H) 2.92 (s, 4 H) 3.04 (br. s, 2 H) 3.17 (br. s, 3 H) 7.45 (s, 2 H) 7.74 (s, 1 H) 8.05 (s, 1 H). b) 3-amino-/V-methyl-4-{2-[2-(methyloxy)ethyl]-1-piperidinyl}benzenesulfon
Figure imgf000123_0001
To a solution of A/-methyl-4-{2-[2-(methyloxy)ethyl]-1 -piperidinyl}-3- nitrobenzenesulfonamide (285 mg, 0.80 mmol) in EtOH (5 ml.) was added Pd/C (14 mg, 0.08 mmol). The solution was put on a Parr shaker under 35 psi of H2 at rt for 40 min. The mixture was filtered through a Celite® pad, concentrated, and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (192 mg, 74%) as a white foamy solid. LCMS (ES) m/z 328 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=7.58 Hz, 2 H) 1.50 (br. s, 2 H) 1 .61 (br. s, 2 H) 1.72 (br. s, 1 H) 1.85 (br. s, 1 H) 2.39 (d, J=5.05 Hz, 3 H) 2.94 (br. s, 1 H) 3.07 (s, 3 H) 3.13 - 3.28 (m, 4 H) 5.23 (br. s, 2 H) 6.88 - 6.98 (m, 1 H) 7.06 - 7.22 (m, 3 H). c) A/-methyl-4-{2-[2-(methyloxy)ethyl]-1 -piperidinyl}-3-(1 H-purin-6- ylamino)benzenesulfonamide
To a solution of 3-amino-/V-methyl-4-{2-[2-(methyloxy)ethyl]-1- piperidinyl}benzenesulfonamide (80 mg, 0.24 mmol) and 6-chloro-1 /-/-purine (45 mg, 0.29 mmol) in 1 ,4-dioxane (5 ml.) in a microwave reaction tube was added AgOTf (188 mg, 0.73 mmol). The reaction vessel was sealed and heated at 100 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was further purified by reverse phase HPLC using 5-35% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated, made basic with a solution of ΝΗ3·Η20 in MeOH and washed with water to afford the title compound (27 mg, 24%) as a light yellow solid. LCMS (ES) m/z 406 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .36 - 1.57 (m, 4 H) 1 .72 (br. s, 2 H) 1.85 (br. s, 1 H) 2.00 (br. s, 1 H) 2.48 (d, J=5.05 Hz, 3 H) 2.68 (d, J=6.57 Hz, 1 H) 2.95 - 2.97 (m, 1 H) 3.02 (s, 3 H) 3.15 (d, J=6.32 Hz, 2 H) 3.19 - 3.28 (m, 1 H) 7.42 - 7.49 (m, 2 H) 7.51 (d, J=8.34 Hz, 1 H) 8.36 (s, 1 H) 8.52 (s, 1 H) 9.26 (br. s, 1 H) 9.41 (br. s, 1 H) 13.34 (br. s, 1 H). EXAMPLE 67
4-[2-(2-hydroxyethyl)-1-piperidinyl]-/V-methyl-3-(1 H-purin-6-ylamino)be
Figure imgf000124_0001
a) 4-[2-(2-hydroxyethyl)-1 -piperidinyl]-/V-methyl-3-nitrobenzenesulfonamide
Figure imgf000124_0002
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (300 mg, 1 .28 mmol) in 1 ,4-dioxane (10 mL) was added 2-(2-piperidinyl)ethanol (199 mg, 1.54 mmol). The mixture was heated at 1 10 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (10-80% EtOAc/hexanes) to afford the title compound (350 mg, 80%) as a brown oil. LCMS (ES) m/z 344 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 - 1.60 (m, 3 H) 1.73 (br. s, 2 H) 1.87 - 1.95 (m, 1 H) 2.39 (s, 3 H) 2.62 - 2.68 (m, 3 H) 3.01 (d, J=1 1.62 Hz, 3 H) 3.12 - 3.20 (m, 2 H) 5.26 (s, 1 H) 6.91 (dd, J=8.08, 1 .52 Hz, 1 H) 7.06 (d, J=1 .52 Hz, 1 H) 7.14 (d, J=8.08 Hz, 1 H). b) 3-amino-4-[2-(2-hydroxyethyl)-1 -piperidinyl]-/\/-methylbenzenesulfonamide
Figure imgf000124_0003
To a solution of 4-[2-(2-hydroxyethyl)-1 -piperidinyl]-/V-methyl-3- nitrobenzenesulfonamide (350 mg, 1.02 mmol) in EtOH (10 mL) was added Pd/C (1 1 mg, 0.10 mmol). The solution was put on a Parr shaker under 35 psi of H2 at rt for 40 min. The mixture was filtered through a Celite® pad, concentrated, and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (269 mg, 84%) as a white foamy solid. LCMS (ES) m/z 314 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (br. s, 3 H) 1.78 (br. s, 3 H) 1 .93 - 2.09 (m, 2 H) 2.42 (d, J=3.79 Hz, 3 H) 2.93 (br. s, 2 H) 3.31 (d, J=6.32 Hz, 6 H) 7.02 (d, J=8.34 Hz, 1 H) 7.21 (br. s, 1 H) 7.35 (br. s, 1 H). c) 4-[2-(2-hydroxyethyl)-1-piperidinyl]-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
To a solution of 3-amino-4-[2-(2-hydroxyethyl)-1-piperidinyl]-/\/- methylbenzenesulfonamide (200 mg, 0.64 mmol) and 6-ch I oro-1 /-/-purine (108 mg, 0.70 mmol) in 1 ,4-dioxane (5 mL) in a microwave reaction tube was added AgOTf (492 mg, 1.91 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid. The solid was purified by reverse phase HPLC eluting with 5-30% CH3CN/water. The collected fractions were pooled, concentrated and made basic with ΝΗ3·Η20 to pH -12. A precipitate formed. The precipitate was triturated with water and CH2CI2 to afford the title compound (43 mg, 15%) as a light yellow solid. LCMS (ES) m/z 432 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 - 1.55 (m, 4 H) 1.72 (br. s, 1 H) 1.75 (s, 1 H) 1.83 (m, 1 H) 2.02 (d, J=3.03 Hz, 1 H) 2.48 - 2.50 (m, 3 H) 2.69 (d, J=7.83 Hz, 1 H) 2.95 (d, J=1 1.37 Hz, 1 H) 3.16 (s, 1 H) 3.24 - 3.32 (m, 2 H) 4.31 (t, J=5.05 Hz, 1 H) 7.42 - 7.49 (m, 2 H) 7.49 - 7.55 (m, 1 H) 8.36 (s, 1 H) 8.52 (s, 1 H) 9.27 (d, J=2.02 Hz, 1 H) 9.43 (s, 1 H) 13.37 (br. s, 1 H).
EXAMPLE 68
4-(3-hydroxy-1 -piperidinyl)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000125_0001
To a solution of 4-fluoro-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 mL) in a microwave reaction tube was added 3-piperidinol (31 mg, 0.31 mmol). The reaction vessel was sealed and heated at 130 °C for 3 d. The mixture was cooled to rt and purified by reverse phase HPLC eluting with 5-25% CH3CN in water with 0.1 % TFA to afford a brown oil. The oil was dissolved in MeOH and made basic to a pH~12 with NH4OH. A yellow precipitate formed. The solid was triturated with water, CH2CI2, and hexanes to afford the title compound (40 mg, 30%) as an off-white solid. LCMS (ES) m/z 404 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .35 (br. s, 1 H) 1.72 (br. s, 1 H) 1.84 (br. s, 1 H) 1 .97 (br. s, 1 H) 2.46 (d, J=5.05 Hz, 3 H) 2.58 (d, J=9.35 Hz, 1 H) 2.66 - 2.76 (m, 1 H) 2.94 (d, J=1 1 .37 Hz, 1 H) 3.08 (br. s, 1 H) 3.79 (dd, J=8.59, 4.55 Hz, 1 H) 4.95 (d, J=4.55 Hz, 1 H) 7.34 - 7.49 (m, 3 H) 8.35 (s, 1 H) 8.50 (s, 1 H) 8.86 (s, 1 H) 9.06 (d, J=2.02 Hz, 1 H) 13.36 (br. s, 1 H).
EXAMPLE 69
4-(4-hydroxy-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide
Figure imgf000126_0001
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 mL) in a microwave reaction tube was added 4- piperidinol (31 mg, 0.31 mmol). The reaction vessel was sealed and heated at 150 °C for 2 h. The mixture was cooled to rt and purified by reverse phase HPLC eluting with 5-20% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated to -0.5 mL and treated with NH4OH. A precipitate formed. The precipitate was triturated with water and CH2CI2 to afford the title compound (32 mg, 24%) as a tan solid. LCMS (ES) m/z 404 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70 (d, J=9.60 Hz, 2 H) 1 .92 (br. s, 1 H) 1.98 (br. s, 1 H) 2.46 (d, J=4.80 Hz, 3 H) 2.78 (br. s, 2 H) 3.09 (br. s, 2 H) 3.71 (br. s, 1 H) 4.83 (d, J=3.03 Hz, 1 H) 7.39 - 7.51 (m, 3 H) 8.36 (s, 1 H) 8.50 (s, 1 H) 8.85 (br. s, 1 H) 9.12 (br. s, 1 H) 13.26 (br. s, 1 H). EXAMPLE 70
4-[2-(hydroxymethyl)-1 -pyrrolidine^
Figure imgf000127_0001
A mixture of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (0.3 g, 0.93 mmol) and 2-pyrrolidinylmethanol (0.282 g, 2.79 mmol) in NMP (2.33 mL) was stirred at 1 10 °C in a sealed high pressure vessel for 72 h. The reaction mixture became homogeneous and turned a dark brown. The reaction mixture was dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-100% of a 90:9:1 solution of CHCl3:MeOH:NH4OH in CHCI3. The desired fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH and CH2CI2 was added to crash out the title compound from solution. The white precipitate that formed was collected by suction filtration and dried in vacuo to afford the title compound (1 10 mg, 29%) as a white solid. LCMS (ES) m/e 404.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 - 1.75 (1 H, m) 1.75 - 1.90 (2 H, m) 1 .91 - 2.04 (1 H, m) 2.43 (3 H, d, J=5.05 Hz) 2.95 - 3.06 (1 H, m) 3.34 - 3.57 (3 H, m) 3.91 (1 H, br. s) 4.50 (1 H, br. s) 7.09 - 7.27 (2 H, m) 7.43 (1 H, dd, J=8.72, 2.15 Hz) 7.98 (1 H, d, J=1.77 Hz) 8.13 - 8.37 (2 H, m) 9.20 (1 H, br. s) 13.13 (1 H, br. s).
EXAMPLE 71
4-(cycloheptyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000127_0002
a) 4-(cycloheptyloxy)-/V-methyl-3-nitrobenzenesulfonamide
Figure imgf000128_0001
A solution of cycloheptanol (2.57 mL, 21 .35 mmol) and NaH (60% dispersion in oil, 188 mg, 4.70 mmol) stirred for 15 min at rt. Then a solution of 4-fluoro-/V-methyl-3- nitrobenzenesulfonamide (500 mg, 2.135 mmol) in 1 ,4-dioxane (5 mL) was added to the reaction mixture and stirred for 1 h at 24 °C in a sealed tube. The reaction was quenched with water and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification by flash column chromatography (10-30% EtOAc/Hexanes) afforded the title compound (400 mg, 57%) as a yellow solid. b) 3-amino-4-(cycloheptyloxy)-/V-meth lbenzenesulfonamide
Figure imgf000128_0002
A solution of 4-(cycloheptyloxy)-/V-methyl-3-nitrobenzenesulfonamide (400 mg, 1.218 mmol) and zinc (558 mg, 8.53 mmol) in AcOH (6 mL) and MeOH (1 mL) stirred for 1 h at 50 °C. The reaction mixture was filtered and concentrated in vacuo to afford the title compound (370 mg, 85%) as an orange oil. c) 4-(cycloheptyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
A solution of 3-amino-4-(cycloheptyloxy)-/\/-methylbenzenesulfonamide (370 mg, 1.240 mmol), 6-chloro-1 H-purine (192 mg, 1 .240 mmol), and AcOH (0.444 mL, 6.20 mmol) in 1 ,4-dioxane (5 mL) was heated at 100 °C for 18 h in a sealed tube. The reaction mixture was adsorbed onto silica gel, concentrated to dryness, and then purified by flash column chromatography [0-80%: (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3]. The resulting solid was triturated with CH2CI2 and then further purified by reverse phase HPLC to afford the title compound (13 mg, 2.5%) as a pale yellow solid. LCMS (ES) m/e 417 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1 .63 (m, 6 H) 1 .69 (s, 2H) 1.76-1 .90 (m, 2H) 2.45 (d, J=5.05 Hz, 3H) 4.70-7.89 (m, 1 H) 7.28 (d, J=8.84 Hz, 1 H) 7.36 (q, J=4.80 Hz, 1 1-1) 8.34 (s, 11-1) 8.57 (s, 2H) 9.02 (s, 1 H) 13.36 (s, 1 H).
EXAMPLE 72
/V-methyl-4-[(1-methylpropyl)oxy]-3-(1 H-purin-6-ylamino)be
Figure imgf000129_0001
a) A/-methyl-4-[(1-methylpropyl)oxy]-3-nitrobenzenesulfonamide
Figure imgf000129_0002
A solution of 2-butanol (1.96 ml_, 21 .35 mmol) and NaH (60% dispersion in oil, 188 mg, 4.70 mmol) stirred for 15 min at rt. Then a solution of 4-fluoro-/V-methyl-3- nitrobenzenesulfonamide (500 mg, 2.135 mmol) in 1 ,4-dioxane (5 ml_) was added to the reaction mixture and stirred for 1 h at 24 °C in a sealed tube. The reaction was quenched with water and extracted with CH2CI2 (3 x 25 ml_). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification by flash column chromatography (20-40% EtOAc/Hexanes) afforded the title compound (460 mg, 75%) as a yellow solid. b) 3-amino-/V-methyl-4-[(1 -methylpro l)oxy]benzenesulfonamide
Figure imgf000129_0003
A solution of A/-methyl-4-[(1 -methylpropyl)oxy]-3-nitrobenzenesulfonamide (460 mg, 1 .595 mmol) and zinc (730 mg, 1 1 .17 mmol) in AcOH (6 ml.) and MeOH (1 ml.) stirred for 1 h at rt. The reaction was filtered and concentrated in vacuo to afford the title compound (550 mg, 75%) as an orange oil. c) A/-methyl-4-[(1 -methylpropyl)oxy]-3-(1 H-purin-6-ylamino)benzenesulfonamide
A solution of 3-amino-/V-methyl-4-[(1 -methylpropyl)oxy]benzenesulfonamide (550 mg, 2.129 mmol), 6-chloro-1 H-purine (329 mg, 2.129 mmol), and AcOH (0.762 mL, 10.65 mmol) in 1 ,4-dioxane (6 mL) was heated at 100 °C for 18 h in a sealed tube. The reaction mixture was adsorbed onto silica gel, concentrated to dryness, and then purified by flash column chromatography [50-100%: (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3]. The resulting solid was triturated with CH2CI2 and then further purified by reverse phase HPLC to afford the title compound (100 mg, 12.5%) as a pale yellow solid. LCMS (ES) m/e 377 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=4.45 Hz, 3H) 1.34 (d, J=6.06Hz, 3H) 1.61 -1.85 (m, 2H) 2.08 (s, 1 H) 2.45 (d, J=5.05 Hz, 3H) 4.53-4.77 (m, 1 H) 7.24-7.41 (m, 2H) 7.46 (dd, J=8.59, 2.27 Hz 1 H) 8.34 (s, 1 H) 8.48 (s, 1 H) 9.66 (s, 1 H) 13.35 (s, 1 H).
EXAMPLE 73
4-[(1 ,2-dimethylpropyl)oxy]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide
Figure imgf000130_0001
a) 4-[(1 ,2-dimethylpropyl)oxy]-/V-meth l-3-nitrobenzenesulfonamide
Figure imgf000130_0002
A solution of 3-methyl-2-butanol (2.3 mL, 21.35 mmol) and NaH (60% dispersion in oil, 188 mg, 4.70 mmol) stirred for 15 min at rt. Then a solution of 4-fluoro-/V-methyl-3- nitrobenzenesulfonamide (500 mg, 2.135 mmol) in 1 ,4-dioxane (5 mL) was added to the reaction mixture and stirred for 1 h at 24 °C in a sealed tube. The reaction was quenched with water and extracted with CH2CI2 (3 x 25 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification by flash column chromatography (20-40% EtOAc/Hexanes) afforded the title compound (340 mg, 52%) as a yellow solid. b) 3-amino-4-[(1 ,2-dimethylpropyl)ox -/V-methylbenzenesulfonamide
Figure imgf000131_0001
A solution of 4-[(1 ,2-dimethylpropyl)oxy]-/\/-methyl-3-nitrobenzenesulfonamide (340 mg, 1 .125 mmol) and zinc (515 mg, 7.87 mmol) in AcOH (5 mL) and MeOH (1 mL) stirred for 1 h at rt. The reaction was filtered and concentrated in vacuo to afford the title compound (310 mg, 90%) as a colorless oil. c) 4-[(1 ,2-dimethylpropyl)oxy]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide
A solution of 3-amino-4-[(1 ,2-dimethylpropyl)oxy]-/\/-methylbenzenesulfonamide (310 mg, 1.138 mmol), 6-chloro-1 H-purine (176 mg, 1.138 mmol), and AcOH (0.407 mL, 5.69 mmol) in 1 ,4-dioxane (4 mL) was heated at 100 °C for 18 h in a sealed tube. The reaction mixture was adsorbed onto silica gel, concentrated to dryness, and then purified by flash column chromatography [10-100%: (1 % NH4OH / 9% MeOH / 90% CHCI3) /
CHCI3]. The resulting solid was triturated with CH2CI2 and then further purified by reverse phase HPLC to afford the title compound (100 mg, 12.5%) as a pale yellow solid. LCMS (ES) m/e 391 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (dd, J=14.65, 6.82 Hz, 6H) 1.26 (d, J= 6.06 Hz, 3H) 1.87-2.06 (m, 1 H) 2.46 (d, J=5.05 Hz, 3H) 4.52-4.64 (m, 1 H) 7.27-7.42 (m, 2H) 7.47 (dd, J=8.59, 2.27 Hz, 2H) 8.35 (s, 1 H) 8.61 (s 1 H) 13.42 (s, 1 H).
EXAMPLE 74
A/-methyl-4-{[4-(methyloxy)cyclohexyl]oxy}-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000131_0002
a) /V-methyl-4-{[4-(methyloxy)cyclohex l]oxy}-3-nitrobenzenesulfonamide
Figure imgf000132_0001
A solution of 4-(methyloxy)cyclohexanol (556 mg, 4.27 mmol) and NaH (60% dispersion in oil, 188 mg, 4.70 mmol) stirred for 15 min at rt. Then a solution of 4-fluoro-/V- methyl-3-nitrobenzenesulfonamide (500 mg, 2.135 mmol) in 1 ,4-dioxane (5 mL) was added to the reaction mixture and stirred for 1 h at 24 °C in a sealed tube. The reaction was quenched with water and extracted with CH2CI2 (3 x 25 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (630 mg, 86%) as a yellow oil. b) 3-amino-/V-methyl-4-{[4-(methyloxy cyclohexyl]oxy}benzenesulfonamide
Figure imgf000132_0002
A solution of A/-methyl-4-{[4-(methyloxy)cyclohexyl]oxy}-3- nitrobenzenesulfonamide (630 mg, 1 .829 mmol) and zinc (837 mg, 12.81 mmol) in AcOH (4 mL) and MeOH (1 mL) stirred for 1 h at 50 °C. The reaction mixture was filtered and concentrated in vacuo to afford the title compound (560 mg, 97%) as a pale orange oil. c) A/-methyl-4-{[4-(methyloxy)cyclohexyl]oxy}-3-(1 /-/-purin-6-ylamino)benzenesulfonamide A solution of 3-amino-/V-methyl-4-{[4-(methyloxy)cyclohexyl]oxy}- benzenesulfonamide (560 mg, 1.514 mmol), 6-chloro-1 /-/-purine (234 mg, 1.514 mmol), and AcOH (0.542 mL, 7.57 mmol) in 1 ,4-dioxane (5 mL) was heated at 100 °C for 18 h in a sealed tube. The reaction was neutralized with sat. aq. NaHC03, filtered, and purified by reverse phase HPLC. The resultant compound was adsorbed onto silica gel, concentrated to dryness, and then further purified by flash column chromatography (1- 10% MeOH/EtOAc) to afford the title compound (10 mg, 1.5%) as a white solid. LCMS (ES) m/e 433 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1 .52 (m, 1 H) 1.53-1 .66 (m, 1 H) 1.66-1 .82 (m, 3H) 1.84-2.01 (m, 2H) 1.99-2.15 (m, 2H) 2.45 (d, J=4.80 Hz, 3H) 3.24 (d, J=5.56 Hz, 3H) 4.52-4.90 (m, 1 H) 7.35 (s, 2H) 7.43 (d, J=8.59 Hz, 1 H) 8.38-8.50 (m, 2H) 9.06 (d, J=10.86 Hz, 1 H) 13.27 (s, 1 H). EXAMPLE 75
3-[(3-bromo-1 H-pyrazolo[3,4-c/]pyrimidin-4-yl)amino]-/V-methyl-4-[(2,2,2- trifluoroethyl)oxy]benzenesulfonamide
Figure imgf000133_0001
a) 3-[(3-bromo-1 H-pyrazolo[3,4-(^pyrimidin-4-yl)amino]-4-fluoro-/\/- methylbenzenesulfonamide
Figure imgf000133_0002
A solution of 3-amino-4-fluoro-/\/-methylbenzenesulfonamide (1.5 g, 7.34 mmol), 3- bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (1.715 g, 7.34 mmol), and AcOH (2.63 mL, 36.7 mmol) in 1 ,4-dioxane (25 mL) was heated at 100 °C for 18 h in a sealed tube. A white precipitate formed which was filtered and washed with EtOAc to afford the title compound (2.6 g, 88%) as a white solid. b) 3-[(3-bromo-1 H-pyrazolo[3,4-c ]pyrimidin-4-yl)amino]-/\/-methyl-4-[(2,2,2- trifluoroethyl)oxy]benzenesulfonamide
A solution of 2,2,2-trifluoroethanol (0.45 mL, 6.23 mmol) and NaH (60% dispersion in oil, 1 10 mg, 2.74 mmol) was stirred for 30 min at rt. Then 3-[(3-bromo-1 H-pyrazolo[3,4- d]pyrimidin-4-yl)amino]-4-fluoro-/\/-methylbenzenesulfonamide (500 mg, 1.246 mmol) in NMP (5 mL) was added to the reaction mixture which stirred at 1 10 °C for 5 d in a sealed tube. The reaction mixture was adsorbed onto silica gel, concentrated to dryness, and then purified by flash column chromatography [10-70%: (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3]. The resulting solid was triturated with CH2CI2 to afford the title compound (51 mg, 8.5%) as a white solid. LCMS (ES) m/e 483 (M+H)+; 1H NMR (400 MHz, DMSO- cfe) δ ppm 2.45 (d, J= 4.80 Hz, 3H) 5.09 (q, J=8.59 Hz, 2H) 7.40-7.54 (m, 2H) 7.57 (dd, J=8.72, 2.15 Hz 1 H) 8.55 (s, 1 H) 8.71 (s, 1 H) 9.19 (d, J=2.02 Hz, 1 H) 14.26 (s, 1 H). EXAMPLE 76
A/-methyl-3-(1 /-/-purin-6-ylamino)-4-{[4-(trifluoromethyl)cyclohexyl]oxy} benzenesulfonamide
Figure imgf000134_0001
a) A/-methyl-3-nitro-4-{[4-(trifluoromethyl)cyclohexyl]oxy}benzenesulfonamide
Figure imgf000134_0002
A solution of 4-(trifluoromethyl)cyclohexanol (1 g, 5.77 mmol) and NaH (60% dispersion in oil, 376 mg, 9.40 mmol) was stirred for 15 min at rt. Then a solution of 4- fluoro-/V-methyl-3-nitrobenzenesulfonamide (1 .0 g, 4.27 mmol) in 1 ,4-dioxane (5 mL) was added to the reaction mixture and was stirred for 18 h at 24 °C in a sealed tube. The reaction was quenched with water and extracted with CH2CI2 (3 x 25 mL). The combined organic layers were dried over Na2S04, filtered, concentrated, and purified by flash column chromatography (20-40% EtOAc/hexanes) to afford the title compound (750 mg, 46%) as a yellow solid. b) 3-amino-/V-methyl-4-{[4-(trifluoromethyl)cyclohexyl]oxy}benzenesulfonamide
Figure imgf000134_0003
A solution of A/-methyl-3-nitro-4-{[4-(trifluoromethyl)cyclohexyl]oxy} benzenesulfonamide (750 mg, 1.27 mmol) and zinc (584 mg, 8.92 mmol) in AcOH (5 mL) and MeOH (2 mL) was stirred for 1 h at rt. The reaction was filtered, concentrated, and purified by flash column chromatography (10-35% EtOAc/Hexanes) to afford the title compound (200 mg, 44%) as an orange oil. c) A/-methyl-3-(1 /-/-purin-6-ylamino)-4-{[4-(trifluoromethyl)cyclohexyl]oxy}
benzenesulfonamide A solution of 3-amino-/V-methyl-4-{[4-(trifluoromethyl)cyclohexyl]oxy}
benzenesulfonamide (200 mg, 0.568 mmol), 6-chloro-1 /-/-purine (88 mg, 0.568 mmol), and AcOH (0.20 mL, 2.84 mmol) in 1 ,4-dioxane (2 mL) was heated at 100 °C for 18 h in a sealed tube. The reaction mixture was adsorbed onto silica gel, concentrated to dryness, and then purified by flash column chromatography [10-70%: (1 % NH4OH / 9% MeOH / 90% CHCIs) / CHCI3]. The resulting solid was triturated with CH2CI2 to afford the title compound (19 mg, 7.2%) as a white solid. LCMS (ES) m/e 471 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .45-1.70 (m, 4H) 1 .97 (s, 2H) 2.24 (d, J=5.56 Hz, 2H) 2.44 (d, J=5.05 Hz, 3H) 4.61 (s, 1 H) 7.29-7.553 (m, 4H) 8.33 (s, 1 H) 8.48 (d, J=9.60 Hz, 2H) 9.02 (s, 1 H) 13.35 (s, 1 H).
EXAMPLE 77
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[(1 ,2-dimethylpropyl)oxy]-/\/- methylbenzenesulfonamide
Figure imgf000135_0001
A solution of 3-amino-4-[(1 ,2-dimethylpropyl)oxy]-/\/-methylbenzenesulfonamide (100 mg, 0.367 mmol), 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (86 mg, 0.367 mmol), and AcOH (0.131 mL, 1.836 mmol) in 1 ,4-dioxane (3 mL) was heated at 100 °C for 18 h in a sealed tube. The reaction mixture was adsorbed onto silica gel, concentrated to dryness and purified by flash column chromatography [40-70%: (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3]. The resulting solid was triturated with CH2CI2 to afford the title compound (80 mg, 46%) as a white solid. LCMS (ES) m/e 471 (M+H)+; 1 H NMR (400 MHz, DMSO-de) δ ppm 0.95 (d, J=6.82 Hz, 3H) 1 .00 (d, J=6.57 Hz, 3H) 1.31 (d, J=6.06 Hz, 3H) 2.04 (dq, J=13.23, 6.71 Hz, 1 H) 2.45 (d, J=5.05 Hz, 3H) 4.59 (q, J=6.13 Hz, 1 H) 7.31-7.43 (m, 2H) 7.51 (dd, J=8.59, 2.27 Hz, 1 H) 8.55 (s, 1 H) 8.77 (s, 1 H) 9.20 (d, J=2.27 Hz, 1 H) 14.23 (s, 1 H).
EXAMPLE 78
3-[(3-bromo-1 /-/-pyrazolo[3,4-c/]pyrimidin-4-yl)amino]-/\/-methyl-4-(4-methyl-1 - piperazinyl)benzenesulfonamide
Figure imgf000136_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/\/- methylbenzenesulfonamide (180 mg, 0.45 mmol) and 1 -methylpiperazine (0.35 mL, 3.14 mmol) in 1 ,4-dioxane (3 mL) was heated at 160 °C under microwave conditions for 2 h. To the reaction mixture was added 1 mL of NMP and the reaction was heated at 1 10 °C for an additional 7 d. After cooling, the precipitate was filtered and washed with CH2CI2 and water to afford the title compound (148 mg, 68.5%) as a white solid. LCMS(ES) m/e 481 ,483(M, M+2); 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.1 1 (s, 1 H), 9.04 (s, 1 H), 8.53 (s, 1 H), 7.53 (s, 2H), 7.48 (d, J = 5.05 Hz, 1 H), 2.94 (t, J = 4.55 Hz, 4H), 2.60 (br. s, 4H), 2.46 (d, J = 4.80 Hz, 3H), 2.26 (s, 3H).
EXAMPLE 79
3-{[3-(3,6-dihydro-2/-/-pyran-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-
(methyloxy)benzenesulfonamide
Figure imgf000136_0002
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide (350 mg, 0.85 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (801 mg, 3.81 mmol), PdCI2(dppf)«CH2CI2 (69 mg, 0.085 mmol) and 2 M aq. K2C03 (2.1 17 ml_, 4.23 mmol) in 1 ,4-dioxane (8 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite®. The residue was purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (232 mg, 65.8%) as a white solid. LCMS(m/e):417 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.85 (br. s, 1 H), 9.28 (d, J = 2.27 Hz, 1 H), 8.54 (s, 1 H), 8.50 (s, 1 H), 7.50 (dd, J = 2.27, 8.59 Hz,
1 H), 7.39 (d, J = 5.05 Hz, 1 H), 7.31 (d, J = 8.59 Hz, 1 H), 6.36 (br. s, 1 H), 4.34 (d, J = 2.53 Hz, 2H), 4.02 (s, 3H), 3.93 (t, J = 5.56 Hz, 2H), 2.59 - 2.70 (m, 2H), 2.44 (d, J = 5.05 Hz, 3H).
EXAMPLE 80
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(1- piperidinyl)benzenesulfonamide
Figure imgf000137_0001
A mixture of 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (220 mg, 0.942 mmol), 3-amino-/V-methyl-4-(1-piperidinyl)benzenesulfonamide (267 mg, 0.989 mmol) and silver trifluoroacetate (271 mg, 1 .225 mmol) in 1 ,4-dioxane (10 mL) was stirred at 80 °C in a sealed tube overnight. The reaction mixture was concentrated onto Celite® and purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (190 mg, 43.2%). LCMS(m/e):
466,468(M, M+2); 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.23 (br. s, 1 H), 9.19 (s, 1 H), 9.06 (s, 1 H), 8.54 (s, 1 H), 7.49 - 7.56 (m, 2H), 7.46 (q, J = 4.97 Hz, 1 H), 2.83 - 2.92 (m, 4H), 2.46 (d, J = 5.05 Hz, 3H), 1 .73 - 1 .83 (m, 4H), 1.58 (br. s, 2H). EXAMPLE 81
3-[(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[3-(h^
methylbenzenesulfonamide
Figure imgf000138_0001
A mixture of 3-[(3-bromo-1/-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/\/- methylbenzenesulfonamide (180 mg, 0.45 mmol) and 3-piperidinylmethanol (517 mg, 4.5 mmol) in NMP (2 ml.) was heated at 110 °C for 7 d. The crude mixture was purified by reverse phase HPLC using 10-80 CH3CN/water (0.1% TFA in mobile phase). The desired fractions were concentrated, diluted with MeOH and NH4OH to make the solution basic, and then reconcentrated. The residue was triturated with water, and the resulting solid was filtered and washed with water and CH2CI2 to afford the title compound (140 mg, 62.9%) as a yellow solid. LCMS(m/e): 496, 498 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δρρπΊ 14.17 (br. s, 1H), 9.17 (s, 1H), 9.07 (d, J= 1.26 Hz, 1H), 8.51 -8.58 (m, 1H), 7.49- 7.58 (m, 2H), 7.46 (q, J = 4.97 Hz, 1H), 4.48 (t, J = 5.18 Hz, 1H), 3.34 - 3.39 (m, 1H), 3.19 -3.29 (m, 1H), 3.09-3.19 (m, 1H), 3.01 (d, J = 11.12 Hz, 1H), 2.61 -2.74 (m, 1H), 2.42- 2.49 (m, 4H), 2.01 (br. s, 1H), 1.71 - 1.88 (m, 3H), 0.99-1.15 (m, 1H). EXAMPLE 82
3-[(3-bromo-1/-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[4-(hydroxymethyl)-1-piperidinyl]-/\/- methylbenzenesulfonamide
Figure imgf000138_0002
A mixture of 3-[(3-bromo-1/-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/\/- methylbenzenesulfonamide (180 mg, 0.449 mmol) and 4-piperidinylmethanol (362 mg, 3.14 mmol) in NMP (2 mL) was heated at 110 °C for 7 d. The crude mixture was purified by reverse phase HPLC using 5-80% CH3CN/water (0.1 % TFA in mobile phase). The desired fractions were concentrated, diluted with MeOH and NH4OH to make the solution basic, and then reconcentrated. The residue was triturated with water, and the resulting solid was filtered and washed with water and CH2CI2 to afford the title compound (142 mg, 63.8%) as a yellow solid. LCMS(m/e): 496, 498 (M, M+2); 1 H NMR (400 MHz, DMSO-d6) δ ρρπΊ 14.24 (br. s, 1 H), 9.25 (s, 1 H), 9.10 (s, 1 H), 8.54 (s, 1 H), 7.50 - 7.56 (m, 2H), 7.46 (q, J = 4.97 Hz, 1 H), 4.55 (t, J = 5.31 Hz, 1 H), 3.36 (br. s, 2H), 3.05 (d, J = 10.86 Hz, 2H), 2.75 (t, J = 10.48 Hz, 2H), 2.46 (d, J = 5.05 Hz, 3H), 1.78 (d, J = 8.84 Hz, 2H), 1.52 - 1.65 (m, 3H).
EXAMPLE 83
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(4-hydroxy-1 -piperidinyl)-/\/- methylbenzenesulfonamide
Figure imgf000139_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/\/- methylbenzenesulfonamide (180 mg, 0.449 mmol) and 4-piperidinol (318 mg, 3.14 mmol) in NMP (2 mL) was heated at 1 10 °C for 7 d. The crude mixture was purified by reverse phase HPLC using 5-80% CH3CN/water (0.1 % TFA in mobile phase), the desired fractions were concentrated, diluted with MeOH and NH4OH to make the solution basic, and then reconcentrated. The residue was triturated with water, and the resulting solid was filtered and washed with water and CH2CI2 to afford the title compound (1 17 mg, 54.1 %) as a yellow solid. LCMS (m/e): 482,484(M, M+2); 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.22 (br. s, 1 H), 9.20 (s, 1 H), 9.10 (d, J = 1.52 Hz, 1 H), 8.54 (s, 1 H), 7.49 - 7.57 (m, 2H), 7.46 (q, J = 4.80 Hz, 1 H), 4.75 (d, J = 4.80 Hz, 1 H), 3.62 - 3.77 (m, 1 H), 2.97 - 3.1 1 (m, 2H), 2.73 - 2.85 (m, 2H), 2.46 (d, J = 5.05 Hz, 3H), 1 .87 - 2.02 (m, 2H), 1 .66 - 1 .80 (m, 2H). EXAMPLE 84
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(3-hy
methylbenzenesulfonamide
Figure imgf000140_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/\/- methylbenzenesulfonamide (180 mg, 0.45 mmol), 3-piperidinol (318 mg, 3.14 mmol) and /'- Pr2NEt (0.5 ml.) in NMP (2 ml.) was heated at 130 °C overnight, and then further heated at 150 °C over the weekend. The crude mixture was purified by reverse phase HPLC using 5-80% CH3CN/water (0.1 % TFA in mobile phase). The desired fractions were concentrated, diluted with MeOH and NH4OH, and then reconcentrated. The residue was triturated with water, and the resulting solid was filtered and washed with water to afford the title compound (98 mg, 45.3%) as a yellow solid. LCMS(m/e): 482, 484 (M, M+2); 1H NMR (400 MHz, DMSO-d6 + D20 (one drop)) δ ppm 8.98 (d, J = 2.02 Hz, 1 H), 8.51 (s,
1 H), 7.39 - 7.58 (m, 2H), 3.83 (dt, J = 4.89, 9.16 Hz, 1 H), 3.02 - 3.1 1 (m, 1 H), 2.90 (d, J = 1 1 .12 Hz, 1 H), 2.58 - 2.72 (m, 1 H), 2.46 - 2.50 (m, 1 H), 2.44 (s, 3H), 1.93 (br. s, 1 H), 1.79 (d, J = 18.44 Hz, 2H), 1 .30 (br. s, 1 H).
EXAMPLE 85
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylpropyl)oxy]benzenesulfonamide
Figure imgf000140_0002
To 2-butanol (0.42 mL, 4.49 mmol) was added NaH (60% dispersion in oil, 126 mg, 3.14 mmol) in NMP (2.5 mL). After stirring at rt for 30 min, 3-[(3-bromo-1 H- pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-fluoro-/\/-methylbenzenesulfonamide (180 mg, 0.45 mmol) was added. The mixture was stirred at rt for 30 min and then heated at 1 10 °C for 20 h. The mixture was cooled to rt and 1.5 ml. of DMSO was added. The reaction contents were filtered through Celite®. The liquid residue was purified by reverse phase HPLC using 5-90% CH3CN/water (0.1 % TFA in mobile phase). The desired fractions were concentrated, diluted with MeOH and NH4OH, and reconcentrated. The residue was triturated with water, and the resulting solid was filtered and washed with water to afford the title compound (13 mg, 6.36%) as white solid. LCMS(m/e): 455,457(M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.25 (br. s, 1 H), 9.26 (d, J = 2.27 Hz, 1 H), 8.82 (s, 1 H), 8.56 (s, 1 H), 7.51 (dd, J = 2.27, 8.59 Hz, 1 H), 7.34 - 7.43 (m, 2H), 4.74 (q, J = 6.06 Hz, 1 H), 2.45 (d, J = 5.05 Hz, 3H), 1.67 - 1.88 (m, 2H), 1.37 (d, J = 6.06 Hz, 3H), 0.97 (t, J = 7.45 Hz, 3H).
EXAMPLE 86
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (propyloxy)benzenesulfonamide
Figure imgf000141_0001
To 1 -propanol (4 ml_, 53.2 mmol) was added NaH (60% dispersion in oil, 160 mg, 3.99 mmol). After stirring at rt for 30 min, 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4- yl)amino]-4-fluoro-/V-methylbenzenesulfonamide (200 mg, 0.498 mmol) was added. The mixture was stirred at rt for 30 min and then heated at 100 °C for 3 d. The reaction mixture was concentrated onto Celite® and purified by flash column chromatography using 30-90% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with MeOH to afford the title compound (1 18 mg, 53.6%) as a white solid.
LCMS(m/e): 441 , 443 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (d, J = 2.27 Hz, 1 H), 8.79 (s, 1 H), 8.54 (s, 1 H), 7.52 (dd, J = 2.27, 8.59 Hz, 1 H), 7.39 (d, J = 5.05 Hz, 1 H), 7.32 (d, J = 8.59 Hz, 1 H), 4.20 (t, J = 6.44 Hz, 2H), 2.44 (d, J = 5.05 Hz, 3H), 1.80 - 1.92 (m, 2H), 1 .02 (t, J = 7.33 Hz, 3H). EXAMPLE 87
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(butyloxy)-/\/- methylbenzenesulfonamide
Figure imgf000142_0001
To 1 -butanol (4 mL, 0.50 mmol) was added NaH (60% dispersion in oil, 160 mg, 3.99 mmol). After stirring at rt for 30 min, 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4- yl)amino]-4-fluoro-/V-methylbenzenesulfonamide (200 mg, 0.498 mmol) was added. The mixture was stirred at rt for 30 min and then heated at 100 °C for 3 d. The reaction mixture was concentrated onto Celite® and purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (1 10 mg, 48.5%) as a white solid.
LCMS(m/e): 455, 457 (M, M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 14.25 (br. s, 1 H), 9.20 (d, J = 2.27 Hz, 1 H), 8.79 (s, 1 H), 8.55 (s, 1 H), 7.52 (dd, J = 2.27, 8.59 Hz, 1 H), 7.40 (q, J = 5.05 Hz, 1 H), 7.34 (d, J = 8.84 Hz, 1 H), 4.25 (t, J = 6.32 Hz, 2H), 2.44 (d, J = 5.05 Hz, 3H), 1.79 - 1.89 (m, 2H), 1.50 (dq, J = 7.46, 15.00 Hz, 2H), 0.95 (t, J = 7.33 Hz, 3H).
EXAMPLE 88
4-(4-fluoro-1-piperidinyl)-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000142_0002
a) 4-fluoro-3-nitrobenzenesulfonyl chloride
Figure imgf000142_0003
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (630 mg, 2.69 mmol) in 1 ,4-dioxane (10 mL) in a microwave reaction tube was added 4-fluoropiperidine (555 mg, 5.38 mmol). The mixture was put into the microwave reactor at 150 °C for 2 h. The reaction mixture was concentrated and purified by flash column chromatography (5- 70% EtOAc/hexanes) to afford the title compound (252.7 mg, 30%) as a yellow oil. LCMS (ES) m/z 318 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .84 (d, J=3.28 Hz, 2 H) 1.99 (s, 2 H) 2.42 (d, J=5.05 Hz, 3 H) 3.15 (dd, J=6.69, 4.17 Hz, 2 H) 3.25 - 3.32 (m, 2 H) 3.46 - 3.53 (m, 1 H) 7.46 - 7.54 (m, 2 H) 7.83 (dd, J=8.84, 2.27 Hz, 1 H) 8.14 (d, J=2.27 Hz, 1 H). b) 3-amino-4-(4-fluoro-1-piperidinyl)- -methylbenzenesulfonamide
Figure imgf000143_0001
To a solution of 4-(4-fluoro-1 -piperidinyl)-/V-methyl-3-nitrobenzenesulfonamide
(251 mg, 0.789 mmol) in EtOH (10 mL) was added Pd/C (84 mg, 0.079 mmol). The mixture was put on a Parr Shaker for 40 min. The mixture was filtered through a Celite® pad. The filtrate was concentrated to afford the title compound (189.1 mg, 83%) as a white solid. LCMS (ES) m/z 288 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .84 - 1.97 (m, 2 H) 2.00 (br. s, 2 H) 2.38 (br. s, 3 H) 2.78 (br. s, 2 H) 2.97 (br. s, 2 H) 3.62 - 3.77 (m, 1 H) 5.18 (br. s, 2 H) 6.89 - 6.98 (m, 1 H) 7.01 (d, J=8.08 Hz, 1 H) 7.08 (d, J=2.02 Hz, 2 H). c) 4-(4-fluoro-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide
To a solution of 6-chloro-1 /-/-purine (36.1 mg, 0.234 mmol) and 6-chloro-1 /-/-purine (36.1 mg, 0.234 mmol) in 1 ,4-dioxane (5 mL) in a microwave reaction tube was added AcOH (0.06 mL, 1 .1 1 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-7% MeOH/CHCIs with 0.1 % ΝΗ3·Η20) to afford a yellow solid which was triturated with CH2CI2 to afford the title compound (34.8 mg, 38%) as a light yellow solid. LCMS (ES) m/z 406 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (br. s, 2 H) 2.14 (br. s, 2 H) 2.46 (d, J=5.05 Hz, 3 H) 2.92 (br. s, 2 H) 3.07 (br. s, 2 H) 4.96 (m, 1 H) 7.40 - 7.56 (m, 3 H) 8.36 (s, 1 H) 8.50 (s, 1 H) 8.86 (s, 1 H) 9.09 (s, 1 H) 13.37 (br. s, 1 H). EXAMPLE 89
/V-methyl-4-{3-[(methyloxy)methyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
Figure imgf000144_0001
a) 3-[(methyloxy)methyl]piperidine hyd
Figure imgf000144_0002
To a solution of 1 , 1 -dimethylethyl 4-(hydroxymethyl)-1 -piperidinecarboxylate (1 .5 g, 6.97 mmol) in THF (20 mL) was added NaH (60% dispersion in oil, 0.418 g, 10.45 mmol). After the mixture was stirred at 25 °C for 1 h, iodomethane (0.87 mL, 13.93 mmol) was added. The mixture was stirred at rt for 20 h, concentrated, and purified by flash column chromatography (5-80% EtOAc/hexanes) to afford a colorless oil, which was redissolved into CH2CI2 (5.00 mL) and treated with 2 M HCI in 1 ,4-dioxane (17.42 mL, 34.8 mmol). The mixture was stirred for another 20 h. water was added. The aqueous layer was collected and concentrated to afford the title compound (699.5 mg, 78%) as a white solid. LCMS (ES) m/z 130 (M+H)+; 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .17 - 1.27 (m, 1 H) 1 .59 - 1 .80 (m, 3 H) 2.01 (td, J=7.58, 3.79 Hz, 1 H) 2.55 - 2.65 (m, 1 H) 2.67 - 2.79 (m, 1 H) 3.14 - 3.20 (m, 2 H) 3.20 - 3.30 (m, 5 H) 8.78 (br. s, 1 H) 8.93 (br. s, 1 H). b) A/-methyl-4-{3-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 H-purin-6- ylamino)benzenesulfonamide
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.310 mmol) and 3-[(methyloxy)methyl]piperidine hydrochloride (51 .4 mg, 0.310 mmol) in NMP (1 .0 mL) in a microwave reaction tube was added Et3N (0.31 mmol). The reaction vessel was sealed and heated at 150 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (1 -5% MeOH / CHCI3 containing 0.1 % NH3) to afford a light yellow solid, which was triturated with CH2CI2 to afford the title compound (27.8 mg, 20%) as an off-white solid. LCMS (ES) m/z 432 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1.21 (d, J=14.40 Hz, 1 H) 1 .71 - 1 .89 (m, 3 H) 2.10 (br. s, 1 H) 2.46 (d, J=5.05 Hz, 3 H) 2.54 - 2.60 (m, 1 H) 2.71 (t, J=10.74 Hz, 1 H) 3.00 (d, J=1 1.12 Hz, 1 H) 3.10 (d, J=10.86 Hz, 1 H) 3.17 (s, 3 H) 3.26 - 3.32 (m, 2 H) 7.39 - 7.49 (m, 3 H) 8.36 (s, 1 H) 8.51 (s, 1 H) 8.94 (s, 1 H) 9.12 (d, J=1.77 Hz, 1 H) 13.36 (br. s, 1 H).
EXAMPLE 90
A/-methyl-4-{2-[(methyloxy)methyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
Figure imgf000145_0001
a) 1 ,1 -dimethylethyl 2-(hydroxymethyl)-1-piperidinecarboxylate
Figure imgf000145_0002
To a solution of 2-piperidinylmethanol (2.30 g, 20 mmol) in CH3CN (20 mL) was added Boc20 (4.88 mL, 21.00 mmol). The mixture was stirred at 25 °C for 20 h. The mixture was concentrated to afford the title compound (3.83 g, 89%) as a white wax-like solid. LCMS (ES) m/z 216 (M+H)+ ; 1H NMR (400 MHz, DMSO-c/6) δ ppm 1.19 - 1 .32 (m, 1 H) 1 .38 (s, 9 H) 1 .43 - 1 .52 (m, 2 H) 1 .54 (br. s, 1 H) 1 .76 (d, J=1 1.87 Hz, 1 H) 2.71 (br. s, 1 H) 3.39 (dd, J=6.57, 5.05 Hz, 2 H) 3.49 (ddd, J=10.61 , 8.59, 6.06 Hz, 1 H) 3.82 (br. s, 1 H) 4.03 (br. s, 1 H) 4.66 (t, J=5.68 Hz, 1 H). b) 1 ,1 -dimethylethyl 2-[(methyloxy)meth l]-1 -piperidinecarboxylate
Figure imgf000145_0003
To a solution of 1 , 1 -dimethylethyl 2-(hydroxymethyl)-1 -piperidinecarboxylate (1 .39 g, 6.49 mmol) in THF (10 mL) was added NaH (60% dispersion in oil, 0.18 g, 7.79 mmol). The mixture was stirred at 25 °C for 1 h and treated with iodomethane (0.487 mL, 7.79 mmol). The mixture was stirred at rt for 20 h, concentrated, and purified by flash column chromatography (5-60% EtOAc/hexanes) to afford the title compound (464.0 mg, 31 %) as a colorless oil. LCMS (ES) m/z 230 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .19 - 1.33 (m, 1 H) 1 .38 (s, 9 H) 1.42 - 1.52 (m, 4 H) 1.65 (d, J=9.09 Hz, 1 H) 2.73 (br. s, 1 H) 3.25 (s, 3 H) 3.40 (d, J=7.33 Hz, 2 H) 3.83 (br. s, 1 H) 4.23 (br. s, 1 H). c) 2-[(methyloxy)methyl]piperidine hydrochloride
Figure imgf000146_0001
To a solution of 1 , 1 -dimethylethyl 2-[(methyloxy)methyl]-1 -piperidinecarboxylate (464 mg, 2.02 mmol) in CH2CI2 (10 ml.) was added 4 M HCI in 1 ,4-dioxane (5.06 ml_, 20.23 mmol). The mixture was stirred at 25 °C for 20 h. The mixture was partitioned between water and CH2CI2. The aqueous solution was concentrated, azeotropically dried with toluene and further dried on a high-vacuum line for 5 h to afford the title compound (259.5 mg, 99%) as a light yellow solid. LCMS (ES) m/z 130 (M+H)+; 1 H NMR (400 MHz, DMSO-de) δ ppm 1.39 - 1.52 (m, 2 H) 1.58 (br. s, 1 H) 1.67 - 1.81 (m, 3 H) 2.83 (br. s, 1 H) 3.17 (br. s, 2 H) 3.31 (s, 3 H) 3.46 - 3.53 (m, 2 H) 8.86 (br. s, 2 H). d) A/-methyl-4-{2-[(methyloxy)methyl]-1 -piperidinyl}-3-nitrobenzenesulfonamide
Figure imgf000146_0002
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (366 mg, 1 .56 mmol) and Et3N (4.69 mmol) was added 2-[(methyloxy)methyl]piperidine hydrochloride (259 mg, 1.56 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (10-80%
EtOAc/hexanes) to afford the title compound (399 mg, 74%) as a yellow oil. LCMS (ES) m/z 344 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 - 1.58 (m, 3 H) 1 .66 - 1 .80 (m, 3 H) 2.40 (d, J=5.05 Hz, 3 H) 2.95 - 2.99 (m., 1 H) 3.10 (s, 3 H) 3.22 - 3.25 (m, 2 H) 3.53 - 3.60 (m., 2 H) 3.69 - 3.71 (m 1 H) 7.45 - 7.53 (m, 2 H) 7.75 - 7.77 (s, 1 H) 8.06 (s,
1 H). e) 3-amino-/V-methyl-4-{2-[(methyloxy me
Figure imgf000147_0001
To a solution of /V-methyl-4-{2-[(methyloxy)methyl]-1-piperidinyl}-3- nitrobenzenesulfonamide (390 mg, 1.13 mmol) in EtOH (10 mL) was added Pd/C (20 mg, 0.1 1 mmol). The mixture was put on a Parr shaker under 35 psi of H2 for 40 min. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated to afford the title compound (314 mg, 88%) as a colorless oil. LCMS (ES) m/z 314 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .38 - 1 .53 (m, 2 H) 1 .57 - 1.65 (m, 2 H) 1.67 - 1 .76 (m, 1 H) 1 .84 - 1.93 (m, 1 H) 2.39 (d, J=5.05 Hz, 3 H) 2.52 - 2.60 (m, 1 H) 2.90 - 2.99 (m, 1 H) 3.07 (s, 3 H) 3.15 (s, 1 H) 3.16 - 3.18 (m, 1 H) 5.23 (s, 2 H) 6.91 (dd, J=8.08, 2.27 Hz, 1 H) 7.07 (d, J=2.27 Hz, 1 H) 7.12 - 7.19 (m, 2 H). f) A/-methyl-4-{2-[(methyloxy)methyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
To a solution of 3-amino-/V-methyl-4-{2-[(methyloxy)methyl]-1- piperidinyl}benzenesulfonamide (150 mg, 0.48 mmol) and 6-chloro-1 /-/-purine (74 mg, 0.48 mmol) in 1 ,4-dioxane (10 mL) in a microwave reaction tube was added AcOH (0.03 mL, 0.48 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by reverse phase HPLC eluting with 7-40%
CH3CN/water containing 0.1 % TFA. The collected fractions were pooled, concentrated, and basified to pH -12 with ΝΗ3·Η20. A white precipitate formed. The precipitate was triturated with water to afford the title compound (1 17.5 mg, 57%) as a white solid. LCMS (ES) m/z 432 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (br. s, 1 H) 1.63 (br. s, 1 H) 1 .68 - 1.75 (m, 2 H) 1 .82 - 1 .84 (m, 1 H) 1.94 (br. s, ) 2.48 (d, J=5.05 Hz, 3 H) 2.72 (br. s, 1 H) 2.94 (s, 4 H) 3.04 - 3.12 (m, 1 H) 3.13 - 3.21 (m, 2 H) 7.40 - 7.51 (m, 2 H) 7.60 (d, J=8.34 Hz, 1 H) 8.35 (s, 1 H) 8.51 (s, 1 H) 9.24 (d, J=2.02 Hz, 1 H) 9.46 (s, 1 H) 13.34 (br. s, 1 H). EXAMPLE 91
/V-methyl-4-{4-[2-(methyloxy)ethyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
Figure imgf000148_0001
To a solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (130 mg, 0.40 mmol) in NMP (1.0 mL) in a microwave reaction tube was added 4-[2- (methyloxy)ethyl]piperidine hydrochloride (87 mg, 0.484 mmol) and Et3N (0.169 mL, 1.20 mmol). The reaction mixture was sealed and heated at 150 °C for 20 h. The mixture was concentrated and purified by reverse phase HPLC eluting with 7-40% CH3CN / water containing 0.1 % TFA. The collected fractions were concentrated to ~1 mL and basified to pH -12 with ΝΗ3·Η20. A precipitate formed. The precipitate was filtered and washed with water followed by hexanes to afford the title compound (40.3 mg, 21 %) as a light yellow solid. LCMS (ES) m/z 446 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .46 (d,
J=19.96 Hz, 2 H) 1.55 (t, J=5.31 Hz, 3 H) 1 .83 (d, J=1 1.87 Hz, 2 H) 2.46 (d, J=5.05 Hz, 3 H) 2.73 (t, J=10.99 Hz, 2 H) 3.08 (d, J=1 1.37 Hz, 2 H) 3.24 (s, 3 H) 3.39 - 3.44 (m, 2 H) 7.39 - 7.48 (m, 3 H) 8.36 (s, 1 H) 8.50 (s, 1 H) 8.82 (s, 1 H) 9.12 (s, 1 H) 13.36 (br. s, 1 H). EXAMPLE 92
A/-methyl-4-[3-(methyloxy)-1 -piperidinyl]-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000148_0002
a) 3-(methyloxy)piperidine hydrochloride
Figure imgf000148_0003
•HCI To a solution of 3-piperidinol (300 mg, 2.97 mmol) in CH3CN (20 mL) was added Boc20 (0.69 mL, 2.97 mmol). The mixture was stirred for 20 h and concentrated to afford a colorless oil, which was dissolved in anhydrous THF (20 mL). The solution was cooled to 0 °C and treated with NaH (60% dispersion in oil, 71 mg, 2.97 mmol). The mixture was gradually warmed to rt. After stirring at rt for 0.5 h, iodomethane (421 mg, 2.97 mmol) was added. The mixture was stirred at 25 °C for 20 h. The solution was concentrated and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford a colorless oil which was dissolved in CH2CI2 (20 mL) and treated with a 2 M solution of HCI in 1 ,4- dioxane (7.41 mL, 14.83 mmol). After stirring at 25 °C for 20 h, the solution was concentrated and azeotropically dried using toluene to afford the title compound (236.4 mg, 53%) as a white solid. LCMS (ES) m/z 152 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (br. s, 2 H) 1 .78 (d, J=7.83 Hz, 2 H) 2.93 (br. s, 2 H) 3.08 - 3.20 (m, 1 H) 3.27 (s, 3 H) 3.53 (br. s, 2 H) 8.80 (br. s, 1 H) 9.47 (br. s, 1 H). b) A/-methyl-4-[3-(methyloxy)-1 -piperidin l]-3-nitrobenzenesulfonamide
Figure imgf000149_0001
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (187 mg, 0.8 mmol) and Et3N (2.4 mmol) was added 3-(methyloxy)piperidine hydrochloride (136 mg, 0.90 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (5-80% EtOAc/hexanes) to afford the title compound (206.5 mg, 78%) as a yellow oil. LCMS (ES) m/z 330 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .41 - 1.59 (m, 2 H) 1 .77 (br. s, 1 H) 1 .99 (s, 1 H) 2.41 (d, J=5.05 Hz, 3 H) 2.88 (dd, J=12.25, 7.45 Hz, 1 H) 2.97 - 3.08 (m, 1 H) 3.17 - 3.28 (m, 4 H) 3.38 - 3.48 (m, 2 H) 7.40 - 7.53 (m, 2 H) 7.80 (dd, J=8.84, 2.27 Hz, 1 H) 8.1 1 (d, J=2.27 Hz, 1 H). c) 3-amino-/V-methyl-4-[3-(methyloxy -1-piperidinyl]benzenesulfonamide
Figure imgf000149_0002
To a solution of /V-methyl-4-[3-(methyloxy)-1 -piperidinyl]-3- nitrobenzenesulfonamide (200 mg, 0.607 mmol) in EtOH (10 ml.) was added Pd/C (6 mg, 0.06 mmol). The mixture was put on a Parr Shaker under 35 psi of H2 for 45 min. The catalyst was removed by filtration. The filtrate was concentrated to afford the title compound (140 mg, 77%) as a solid. LCMS (ES) m/z 300 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1.31 - 1.45 (m, 1 H) 1.59 - 1.68 (m, 1 H) 1.76 (dd, J=8.46, 3.41 Hz, 1 H) 1.95 (br. s, 1 H) 2.38 (br. s, 3 H) 2.54 - 2.59 (m, 1 H) 2.92 - 3.02 (m, 1 H) 3.14 (d, J=10.86 Hz, 1 H) 3.27 - 3.32 (m, 3 H) 3.40 - 3.51 (m, 2 H) 5.13 (s, 2 H) 6.91 - 6.95 (m, 1 H) 6.97 - 7.02 (m, 1 H) 7.07 (d, J=2.02 Hz, 1 H) 7.13 (br. s, 1 H). d) A/-methyl-4-[3-(methyloxy)-1 -piperidinyl]-3-(1 H-purin-6-ylamino)benzenesulfonamide
To a solution of 3-amino-/V-methyl-4-[3-(methyloxy)-1- piperidinyl]benzenesulfonamide (100mg, 0.33 mmol) and 6-chloro-1 /-/-purine (51 mg, 0.33 mmol) in 1 ,4-dioxane (10 ml.) in a sealed tube was added AcOH (0.10 ml_, 1.67 mmol). The mixture was heated at 1 10 °C for 20 h. The mixture was concentrated and purified by reverse phase HPLC eluting with 5-40% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated and further purified by flash column chromatography (10-80% MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (28.6 mg, 19%) as a light yellow solid. LCMS (ES) m/z 418 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .39 (br. s, 1 H) 1 .72 (br. s, 1 H) 1 .86 (br. s, 1 H) 2.46 (d, J=5.05 Hz, 3 H) 2.59 - 2.66 (m, 1 H) 2.70 (d, J=1 1 .12 Hz, 1 H) 3.00 (br. s, 1 H) 3.43 (m, 2 H) 7.37 - 7.56 (m, 3 H) 8.36 (s, 1 H) 8.49 (s, 1 H) 8.82 (br. s, 1 H) 9.07 (br. s, 1 H) 13.35 (br. s, 1 H). EXAMPLE 93
A/-methyl-4-[4-(methyloxy)-1 -piperidinyl]-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000150_0001
a) 4-(methyloxy)piperidine hydrochlori
Figure imgf000150_0002
To a solution of 4-piperidinol (500 mg, 4.94 mmol) in CH3CN (20 mL) was added Boc20 (1.15 mL, 4.94 mmol). The mixture was stirred for 20 h and concentrated to afford a colorless oil, which was dissolved in anhydrous THF (20 mL). The solution was cooled to 0 °C and treated with NaH (60% dispersion in oil, 29 mg, 7.41 mmol). The mixture was gradually warmed to rt. After stirring at rt for 0.5 h, iodomethane (1403 mg, 9.89 mmol) was added. The mixture was stirred at 25 °C for 20 h. The solution was concentrated and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford a colorless oil which was dissolved in CH2CI2 (20 mL) and treated with a 2 M solution of HCI in 1 ,4- dioxane (12.4 mL, 24.72 mmol). After stirring at 25 °C for 20 h, the solution was concentrated and azeotropically dried with toluene to afford the title compound (260.8 mg, 33%) as a white solid. LCMS (ES) m/z 152 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.59 - 1.80 (m, 2 H) 1 .90 - 2.04 (m, 2 H) 2.92 (br. s, 2 H) 3.09 (br. s, 2 H) 3.23 - 3.30 (m, 3 H) 3.40-3.41 (m, 1 H) 9.03 (d, J=3.03 Hz, 2 H). b) A/-methyl-4-[4-(methyloxy)-1 -piperidinyl]-3-nitrobenzenesulfonamide
Figure imgf000151_0001
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (300 mg, 1 .281 mmol) and Et3N (3.84 mmol) was added 4-(methyloxy)piperidine hydrochloride (194 mg, 1.281 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (5-80% EtOAc/hexanes) to afford the title compound (227.4, 54%) as a yellow oil. LCMS (ES) m/z 330 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 - 1.61 (m, 2 H) 1.89 - 1.97 (m, 2 H) 2.41 (d, J=4.80 Hz, 3 H) 2.98 - 3.08 (m, 2 H) 3.26 - 3.32 (m, 5 H) 3.40 - 3.48 (m, 1 H) 7.44 (d, J=8.84 Hz, 1 H) 7.49 (d, J=5.05 Hz, 1 H) 7.80 (dd, J=8.84, 2.27 Hz, 1 H) 8.12 (d, J=2.27 Hz, 1 H). c) 3-amino-/V-methyl-4-[4-(methylo -1-piperidinyl]benzenesulfonamide
Figure imgf000151_0002
To a solution of A/-methyl-4-[3-(methyloxy)-1 -piperidinyl]-3- nitrobenzenesulfonamide (181 mg, 0.55 mmol) in EtOH (5 mL) was added Pd/C (585 mg, 0.55 mmol). The mixture was put on a Parr Shaker under 35 psi of H2 for 45 min. The catalyst was removed by filtration. The filtrate was concentrated to afford the title compound (120 mg, 73%) as a solid. LCMS (ES) m/z 300 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1.57 (td, J=8.27, 4.42 Hz, 2 H) 1 .89 - 2.01 (m, 2 H) 2.41 (d, J=4.80 Hz, 3 H) 3.03 (ddd, J=12.63, 9.09, 3.03 Hz, 2 H) 3.26 - 3.32 (m, 5 H) 3.43 (dd, J=8.08, 3.54 Hz, 1 H) 7.42 - 7.53 (m, 2 H) 7.80 (dd, J=8.84, 2.27 Hz, 1 H) 8.12 (d, J=2.27 Hz, 1 H). d) A/-methyl-4-[4-(methyloxy)-1 -piperidinyl]-3-(1 H-purin-6-ylamino)benzenesulfonamide
To a solution of 3-amino-/V-methyl-4-[4-(methyloxy)-1- piperidinyl]benzenesulfonamide (100mg, 0.33 mmol) and 6-chloro-1 /-/-purine (51 mg, 0.33 mmol) in 1 ,4-dioxane (10 mL) in a sealed tube was added AcOH (0.10 mL, 1.67 mmol). The mixture was heated at 1 10 °C for 20 h. The mixture was concentrated and purified by reverse phase HPLC eluting with 5-40% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated and further purified by flash column chromatography (10-80% MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (30 mg, 21 %) as a light yellow solid. LCMS (ES) m/z 418 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .73 (d, J=9.35 Hz, 2 H) 2.04 (br. s, 2 H) 2.46 (d, J=5.05 Hz, 3 H) 2.77 - 2.85 (m, 2 H) 3.03 - 3.12 (m, 2 H) 3.29 - 3.32 (m, 3 H) 3.43 (br. s, 1 H) 7.39 - 7.47 (m, 3 H) 8.36 (s, 1 H) 8.50 (s, 1 H) 8.87 (s, 1 H) 9.1 1 (s, 1 H) 13.36 (br. s, 1 H). EXAMPLE 94
A/-methyl-4-{4-[(methyloxy)methyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
Figure imgf000152_0001
a) 4-[(methyloxy)methyl]piperidine hydrochloride
Figure imgf000152_0002
To a solution of 1 , 1 -dimethylethyl 4-(hydroxymethyl)-1 -piperidinecarboxylate (1 .0 g, 4.64 mmol) in THF (20 mL) was added NaH (60% dispersion in oil, 0.279 g, 6.97 mmol). After the mixture was stirred at 25 °C for 1 h, iodomethane (0.581 mL, 9.29 mmol) was added. The mixture was stirred at rt for 20 h, concentrated, and purified by flash column chromatography (5-80% EtOAc/hexanes) to afford a colorless oil which was redissolved into CH2CI2 (5 mL) and treated with 2 M HCI in 1 ,4-dioxane (1 1 .61 mL, 23.22 mmol). The mixture was stirred for another 20 h and concentrated to afford the title compound (313.5 mg, 41 %) as a white solid. LCMS (ES) m/z 130 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1 .28 - 1 .48 (m, 2 H) 1 .67 - 1 .85 (m, 3 H) 2.81 (br. s, 2 H) 3.17 (d, J=6.32 Hz, 3 H) 3.19 - 3.27 (m, 4 H) 8.94 (br. s, 1 H) 9.21 (br. s, 1 H). b) A/-methyl-4-{4-[(methyloxy)meth l]-1-piperidinyl}-3-nitrobenzenesulfonamide
Figure imgf000153_0001
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (150 mg, 0.64 mmol) and Et3N (1.92 mmol) was added 4-[(methyloxy)methyl]piperidine hydrochloride (127 mg, 0.77 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (5-80%
EtOAc/hexanes) to afford the title compound (164.1 mg, 75%) as a yellow oil. LCMS (ES) m/z 344 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=1 1 .62 Hz, 2 H) 1.73 (d, J=12.88 Hz, 3 H) 2.41 (d, J=5.05 Hz, 3 H) 2.98 (br. s, 2 H) 3.18 - 3.28 (m, 5 H) 3.39 (br. s, 2 H) 7.42 (d, J=8.84 Hz, 1 H) 7.48 (d, J=5.05 Hz, 1 H) 7.79 (dd, J=8.84, 2.27 Hz, 1 H) 8.1 1 (d, J=2.02 Hz, 1 H). c) 3-amino-/V-methyl-4-{4-[(methylox methyl]-1-piperidinyl}benzenesulfonamide
Figure imgf000153_0002
To a solution of A/-methyl-4-{4-[(methyloxy)methyl]-1-piperidinyl}-3- nitrobenzenesulfonamide (164 mg, 0.478 mmol) in EtOH (10 mL) was added Pd/C (8.47 mg, 0.048 mmol). The mixture was put on a Parr Shaker under 35 psi of H2 for 40 min. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated to afford the title compound (133.1 mg, 89%) as a colorless oil. LCMS (ES) m/z 314 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 - 1.52 (m, 2 H) 1 .58 - 1.65 (m, 2 H) 1.67 - 1.76 (m, 1 H) 1.84 - 1 .92 (m, 1 H) 2.39 (d, J=5.05 Hz, 3 H) 2.53 - 2.60 (m, 1 H) 2.90 - 2.98 (m, 1 H) 3.07 (s, 3 H) 3.13 - 3.19 (m, 3 H) 5.23 (s, 2 H) 6.91 (dd, J=8.08, 2.27 Hz, 1 H) 7.07 (d, J=2.27 Hz, 1 H) 7.12 - 7.18 (m, 2 H). d) A/-methyl-4-{4-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide To a solution of 3-amino-/V-methyl-4-[3-(methyloxy)-1- piperidinyl]benzenesulfonamide (100mg, 0.33 mmol) and 6-chloro-1 /-/-purine (51 mg, 0.33 mmol) in 1 ,4-dioxane (10 ml.) in a sealed tube was added AcOH (0.10 ml_, 1.67 mmol). The mixture was heated at 1 10 °C for 20 h. The mixture was concentrated and purified by reverse phase HPLC eluting with 5-40% CH3CN/water containing 0.1 % TFA. The collected fractions was concentrated and further purified by flash column chromatography (10-80% MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (12.9 mg, 9%) as a light yellow solid. LCMS (ES) m/z 432 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 - 1.53 (m, 2 H) 1.76 (br. s, 1 H) 1.81 (br. s, 2 H) 2.46 (d, J=5.05 Hz, 3 H) 2.75 (br. s, 2 H) 3.1 1 (d, J=1 1.87 Hz, 2 H) 3.28 (s, 3H) 3.29 (br. s, 2 H) 3.40 (br. s, 1 H) 7.37 - 7.50 (m, 3 H) 8.28 - 8.41 (m, 1 H) 8.50 (s, 1 H) 8.78 (s, 1 H) 9.12 (br. s, 1 H) 13.32 (br. s, 1 H).
EXAMPLE 95
A/-methyl-4-(4-methyl-1 -piperidinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000154_0001
A solution of 4-fluoro-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide (150 mg, 0.46 mmol) in 4-methylpiperidine (46.2 mg, 0.465 mmol) was sealed and heated at 150 °C for 20 h. The mixture was concentrated and purified by reverse phase HPLC eluting with 5-40% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated and further purified by flash column chromatography (10-80% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford the title compound (80.7 mg, 41 %) as an off-white solid. LCMS (ES) m/z 402 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .01 (d, J=6.32 Hz, 3 H) 1.39-1 .50 (m, 2 H) 1 .54 - 1 .62 (m, 2H) 1.78 (d, J=1.37 Hz, 2 H) 2.46 (d, J=5.05 Hz, 2 H) 2.74 (d, J=10.99 Hz, 2 H) 3.07 (d, J=1 1.62 Hz, 2 H) 7.38 - 7.46 (m, 3H) 8.37 (s, 3H) 8.50 (s, 3H) 8.81 (s, 3H) 9.13 (d, J=1.77 Hz, 1 H) 13.36 (br. s, 1 H). EXAMPLE 96
/V-methyl-3-(1 /-/-purin-6-ylamino)-4-[(2,2,2-trifluoroethyl)oxy] benzenesulfonamide
Figure imgf000155_0001
To a solution of 2,2,2-trifluoroethanol (31.0 mg, 0.310 mmol) in THF (1 mL) was added NaH (60% dispersion in oil, 62 mg, 1.55 mmol). The mixture was stirred at rt for 0.5 h and transferred into a solution of 4-fluoro-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in NMP (1 .0 mL). The reaction vessel was sealed, heated at 120 °C for 20 h and purified by flash column chromatography (2-8% MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (18.7 mg, 14%) as a white solid. LCMS (ES) m/z 403 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (d, J=5.05 Hz, 3 H) 5.02 (t, J=8.72 Hz, 2 H) 7.39 - 7.50 (m, 2 H) 7.53 (dd, J=8.72, 2.15 Hz, 1 H) 8.32 (s, 1 H) 8.43 (s, 1 H) 8.65 (s, 1 H) 8.84 (s, 1 H) 13.32 (br. s, 1 H).
EXAMPLE 97
4-(3,5-dimethyl-1-piperidinyl)-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000155_0002
A solution of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (100 mg, 0.31 mmol) in 3,5-dimethylpiperidine (351 mg, 3.10 mmol) was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column
chromatography (0-6% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20). The collected fractions were pooled and concentrated to afford a yellow solid which was further purified by reverse phase HPLC eluting with 5-40% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated and further purified by flash column chromatography (10-80% MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (21 mg, 16%) as an off-white solid. LCMS (ES) m/z 416 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.74 (d, J=1 1 .87 Hz, 1 H) 0.87 (d, J=6.57 Hz, 6 H) 1.94 (d, J=7.33 Hz, 3 H) 2.30 (t, J=1 1 .37 Hz, 2 H) 2.46 (d, J=4.80 Hz, 3 H) 3.01 (br. s, 2 H) 7.36 - 7.47 (m, 3 H) 8.35 (s, 1 H) 8.51 (s, 1 H) 8.93 (s, 1 H) 9.13 (d, J=1.77 Hz, 1 H) 13.35 (br. s, 1 H).
EXAMPLE 98
A/-methyl-3-(1 /-/-purin-6-ylamino)-4-[(3,3,3-trifluoropropyl)oxy]benzenesulfonamide
Figure imgf000156_0001
To a solution of 3,3,3-trifluoropropanol (708 mg, 6.21 mmol) in 1 ,4-dioxane (1 mL) was added NaH (60% dispersion in oil, 124 mg, 3.10 mmol). The mixture was stirred at rt for 0.5 h and transferred into a solution of 4-fluoro-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide (200 mg, 0.62 mmol) in 1 ,4-dioxane (8.0 mL) in a sealed tube and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (0-6% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20). The collected fractions were pooled and concentrated to afford a yellow solid which was further purified by reverse phase HPLC eluting with 5-40% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated and further purified by flash column chromatography (10-80% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford the title compound (19.0 mg, 7%) as an off-white solid. LCMS (ES) m/z 417 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (d, J=4.80 Hz, 3 H) 2.86 - 2.97 (m, 2 H) 4.46 (t, J=5.68 Hz, 2 H) 7.34 - 7.43 (m, 2 H) 7.49 (dd, J=8.59, 2.27 Hz, 1 H) 8.34 (s, 1 H) 8.45 - 8.54 (m, 2 H) 9.04 (br. s, 1 H) 13.17 (br. s, 1 H). EXAMPLE 99
A/-methyl-3-(1 H-purin-6-ylamino)-4-[2-(trifluoromethyl)-1 -pyrrolidinyl] benzenesulfonamide
a) A/-methyl-3-nitro-4-[2-(trifluorometh l)-1-pyrrolidinyl]benzenesulfonamide
Figure imgf000157_0002
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (500 mg, 2.13 mmol) in 1 ,4-dioxane (10 mL) was added 2-(trifluoromethyl)pyrrolidine (315 mg, 2.26 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (5-80% EtOAc/hexanes) to afford the title compound (419.1 mg, 56%) as a yellow oil. LCMS (ES) m/z 354 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .83 (br. s, 1 H) 1 .96 - 2.06 (m, 2 H) 2.31 - 2.39 (m, 1 H) 2.39 - 2.49 (m, 4 H) 2.85 (br. s, 1 H) 5.28 (br. s, 1 H) 7.50 (t, J=4.93 Hz, 1 H) 7.71 - 7.83 (m, 2 H) 8.1 1 (d, J=2.02 Hz, 1 H). b) 3-amino-/V-methyl-4-[2-(trifluorometh l)-1 -pyrrolidinyl]benzenesulfonamide
Figure imgf000157_0003
To a solution of A/-methyl-3-nitro-4-[2-(trifluoromethyl)-1- pyrrolidinyl]benzenesulfonamide (417 mg, 1.180 mmol) in EtOH (10 mL) was added Pd/C (126 mg, 0.1 18 mmol). The mixture was put on a Parr Shaker under 35 psi of H2 for 45 min. The catalyst was removed by filtration. The filtrate was concentrated to afford the title compound (339.2 mg, 89%) as a yellow solid. LCMS (ES) m/z 324 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1.84 - 2.09 (m, 4 H) 2.29 - 2.44 (m, 4 H) 2.65 - 2.78 (m, 1 H) 3.52 (dd, J=7.83, 5.56 Hz, 1 H) 4.46 (br. s, 1 H) 5.20 (br. s, 1 H) 6.90 (dd, J=8.21 , 2.15 Hz, 1 H) 7.09 (d, J=2.02 Hz, 1 H) 7.17 (br. s, 1 H) 7.30 (d, J=8.08 Hz, 1 H). c) /V-methyl-3-(1 H-purin-6-ylamino)-4-[2-(trifluoromethyl)-1 -pyrrolidinyl] benzenesulfonamide
To a solution of 3-amino-/V-methyl-4-[2-(trifluoromethyl)-1- pyrrolidinyl]benzenesulfonamide (339 mg, 1.05 mmol) and 6-chloro-1 /-/-purine (162 mg, 1.05 mmol) in 1 ,4-dioxane (20 mL) was added AcOH (0.30 mL, 5.24 mmol). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (1-7% MeOH/CHCI3 containing 0.1 % TFA) to afford a yellow solid. The yellow solid was further purified by reverse phase HPLC eluting with 20-60% CH3CN/water containing 0.1 % TFA. The collected fractions were concentrated and basified to pH -10 with 2 M NH3 in MeOH. The mixture was concentrated to afford a white solid. The solid was collected and washed with water to afford the title compound (75.7 mg, 16%) as a white solid. LCMS (ES) m/z 442 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .90 - 2.17 (m, 3 H) 2.34 (br. s, 1 H) 2.47 (d, J=5.05 Hz, 3 H) 2.97 (br. s, 1 H) 3.51 (br. s, 1 H) 4.57 (br. s, 1 H) 7.40 - 7.55 (m, 2 H) 7.67 (d, J=8.59 Hz, 1 H) 8.26 - 8.38 (m, 1 H) 8.43 (s, 1 H) 8.87 (d, J=2.02 Hz, 1 H) 9.08 (s, 1 H) 13.30 (br. s, 1 H).
EXAMPLE 100
A/-methyl-3-(1 H-purin-6-ylamino)-4-[(3,3,3-trifl
methylpropyl)oxy]benzenesulfonamide
Figure imgf000158_0001
a) A/-methyl-3-nitro-4-[(3,3,3-trifluor -1-methylpropyl)oxy]benzenesulfonamide
Figure imgf000158_0002
To a solution of 4,4,4-trifluoro-2-butanol (328 mg, 2.56 mmol) in 1 ,4-dioxane (1 m at 0 °C was added NaH (60% dispersion in oil, 68 mg, 1.71 mmol). The mixture was warmed to rt and stirred for 0.5 h. The mixture was treated with a solution of 4-fluoro-/V- methyl-3-nitrobenzenesulfonamide (200 mg, 0.85 mmol) in 1 ,4-dioxane (8 mL). The reaction vessel was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (10-70% EtOAc/hexanes) to afford the title compound (260 mg, 89%) as a brown oil. LCMS (ES) m/z 343 (M+H)+; 1H NMR (400 MHz, DMSO-de) δ ppm 1 .40 (d, J=6.06 Hz, 3 H) 2.44 (d, J=4.80 Hz, 3 H) 2.76 - 2.89 (m, 2 H) 5.10 - 5.22 (m, 1 H) 7.55 - 7.67 (m, 1 H) 7.71 (d, J=8.84 Hz, 1 H) 7.98 (dd, J=8.84 2.27 Hz, 1 H) 8.27 (d, J= 2.27 Hz, 1 H). b) 3-amino-/V-methyl-4-[(3,3,3-trifluoro-1 -methylpropyl)oxy]-1 ,5-cyclohexadiene-1 - sulfonamide
Figure imgf000159_0001
To a solution of A/-methyl-3-nitro-4-[(3,3,3-trifluoro-1- methylpropyl)oxy]benzenesulfonamide (260 mg, 0.76 mmol) in EtOH (10 mL) was added Pd/C (40 mg, 0.038 mmol). The mixture was put on a Parr Shaker under 35 psi of H2 for 45 min. The catalyst was removed by filtration. The filtrate was concentrated to afford the title compound (221 mg, 93%) as a yellow solid. LCMS (ES) m/z 315 (M+H)+ ; 1H NMR (400 MHz, DMSO-de) δ ppm 1.33 (d, J=6.06 Hz, 3 H) 2.37 (d, J=5.05 Hz, 3 H) 2.65 - 2.90 (m, 2 H) 4.80 (ddd, J=7.58, 6.06, 4.04 Hz, 1 H) 5.15 (br. s, 2 H) 6.89 - 6.95 (m, 1 H) 6.99 - 7.06 (m, 2 H) 7.12 (q, J=5.05 Hz, 1 H). c) A/-methyl-3-(1 H-purin-6-ylamino)-4-[(3,3,3-trifluoro-1 -methylpropyl)oxy]
benzenesulfonamide
To a solution of 3-amino-/V-methyl-4-[(3,3,3-trifluoro-1 -methylpropyl)oxy]-1 ,5- cyclohexadiene-1 -sulfonamide (221 mg, 0.70 mmol) and 6-chloro-1 /-/-purine (109 mg, 0.70 mmol) in 1 ,4-dioxane (5 mL) was added AcOH (0.20 mL, 3.52 mmol). The solution was sealed and heated at 1 10 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (1-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a yellow solid which was triturated with CH2CI2 to afford the title compound (130 mg, 41 %) as a white solid. LCMS (ES) m/z 431 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .45 (s, 3 H) 2.46 (d, J=4.80 Hz, 3 H) 2.87 (qd, J=1 1 .12, 6.06 Hz, 2 H) 4.98 - 5.15 (m, 1 H) 7.36 - 7.44 (m, 2 H) 7.48 (dd, J=8.59, 2.27 Hz, 1 H) 8.36 (s, 1 H) 8.48 (s, 2 H) 9.05 (br. s, 1 H) 13.45 (br. s, 1 H). EXAMPLE 101
4-(dimethylamino)-/V-methyl-3-(1 H-py
Figure imgf000160_0001
A mixture of 3-amino-4-(dimethylamino)-/\/-methylbenzenesulfonamide (0.194 g, 0.847 mmol) and 6-chloro-7-deazapurine (0.100 g, 0.651 mmol) in DMF (2 ml.) was treated with AgOTf (0.167 g, 0.651 mmol) and stirred at 80 °C overnight. The mixture was diluted with MeOH, filtered, and subjected to reverse phase HPLC (10-50% CH3CN/aq. NH4OH pH 10, XBridge C18 OBD 30x150 mm, 5 μΐη) to afford slightly impure material (0.089 g, 39.5%) as a pale lavender solid. Further purification by flash column
chromatography (5% MeOH/CH2CI2) afforded the title compound (0.051 g, 22%) as a tan solid. The following compounds were prepared with procedures analogous to that described in Example 101 using the specified chloro-deazapurine and aniline starting materials:
Figure imgf000160_0002
Figure imgf000161_0001
sulfonamide 3-amino-/V-
A/-methyl-4-[(1 -
4-chloro-1 /-/- methyl-4-[(1- methylethyl)oxy]-3-(1 H-
1 12 methylethyl) pyrrolo[2,3-d]pyrimidin-4- 0 0 pyrrolo[2,3-c/]
pyrimidine oxy]benzene ylamino)benzenesulfonamide
sulfonamide
3-amino-/V-
A/-methyl-4-(methylthio)-3-(1 H- 4-chloro-1 /-/- methyl-4-
1 13 pyrrolo[2,3-d]pyrimidin-4- pyrrolo[2,3-cf] (methylthio) ylamino)benzenesulfonamide pyrimidine benzene
Figure imgf000162_0001
sulfonamide
A/-methyl-1-(1 H-pyrrolo[2,3- /V-methyl-2,3-
4-chloro-1 /-/- d]pyrimidin-4-yl)-2,3-dihydro- dihydro-1 /-/-
1 14 o o 1 pyrrolo[2,3-cf]
1 /-/-indole-6-sulfonamide indole-6- pyrimidine
trifluoroacetate sulfonamide
4-chloro-5-
A/-methyl-3-[(5-methyl-1 H- 3-amino-/V- methyM H-
1 15 pyrrolo[2,3-d]pyrimidin-4- methylbenzene pyrrolo[2,3- yl)amino]benzenesulfonamide sulfonamide
Figure imgf000162_0002
cfjpyrimidine
EXAMPLE 1 16
3-[(5-fluoro-1 H-pyrrolo[2,3-(^pyrimidin-4-yl)amino]-/\/-methylbenzenesulfonamide trifluoroacetate
Figure imgf000162_0003
, m n
A mixture of 4-chloro-7-fluoro-7-deazapurine (0.050 g, 0.291 mmol) and /V-methyl 3-aminobenzenesulfonamide (0.070 g, 0.379 mmol) in isopropanol (2 mL) was subjected to microwave irradiation (100 °C, 25 min). The mixture was diluted with MeOH and purified via reverse phase HPLC (10-50% CH3CN/water with 0.1 % TFA) to afford the title compound (0.068 g, 53%) as a white solid. The following compound was prepared with procedures analogous to that described in Example 1 16 using 4-chloro-1 H-pyrrolo[2,3-d]pyrimidine and the specified aniline as starting material:
Figure imgf000163_0002
EXAMPLE 1 18
A/,4-dimethyl-3-(1 /-/-pyrrolo[2,3-c ]pyrimidin-4-ylamino)benzenesulfonamide
Figure imgf000163_0001
A mixture of 3-amino-/V,4-dimethylbenzenesulfonamide (0.227 g, 1.134 mmol) and 4-chloro-1 H-pyrrolo[2,3-c/]pyrimidine (0.174 g, 1.134 mmol) in isopropanol (2.834 ml.) (a few drops of DMF were added to aid solubility) was heated in a microwave reactor at 150 °C for 10 min. AgOTf (0.291 g, 1 .134 mmol) was added and the reaction was heated at 150 °C for 40 additional min in the microwave. The reaction mixture was loaded directly onto a SCX column (loaded in MeOH, filtered prior to loading) and washed with MeOH and then eluted with 10%-50% 2 M NH3 in MeOH in CH2CI2. Concentration of the appropriate fractions yielded a green oil. The residue was suspended in CH2CI2/Et20 and then filtered. The solid was collected to afford the title compound (0.075 g, 20%) as a pale mint green solid. EXAMPLE 1 19
3-[(5-chloro-1 H-pyrrolo[2,3-c/]pyrimidin-4-yl)amino]-/V-methyl-4-(4- morpholinyl)benzenesulfonamide hydrochloride
Figure imgf000164_0001
A mixture of 3-amino-/V-methyl-4-(4-morpholinyl)benzenesulfonamide (0.141 g, 0.519 mmol) isopropanol (1 mL) was treated with 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, 0.399 mmol) and heated at 80 °C overnight. After 18 h, the reaction mixture was cooled to rt and the solid collected by filtration, washed with MeOH, and dried to afford the title compound (0.107 g, 58%) as a pale gray solid.
The following compounds were prepared with procedures analogous to that described in Examplel 19 using the specified chloro-deazapurine and aniline starting materials:
Figure imgf000164_0002
Figure imgf000165_0001
EXAMPLE 126
A/-methyl-3-({5-[4-(methyloxy)phenyl]-1 /-/-pyrrolo[2,3-c/]pyri
yl}amino)benzenesulfonamide trifluoroacetate
Figure imgf000165_0002
•TFA
To a mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-c/]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide (0.200 g, 0.478 mmol), PdCI2(dppf)«CH2CI2 (0.100 g, 0.122 mmol), and (4-methoxyphenyl)boronic acid (218 mg, 1.43 mmol), was added 1 M aq.
Na2C03 (2.5 mL, 2.50 mmol). The resulting mixture was flushed with nitrogen and heated at 100 °C overnight. The reaction mixture was then cooled and treated with water and extracted with EtOAc. The organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The crude material was then dissolved in EtOAc, absorbed onto silica gel, and purified via flash column chromatography (100% EtOAc). The material was then further purified via HPLC (10-50% CH3CN/water with 0.1 % TFA) to afford the title compound (0.028 g, 1 1 %) as a white solid. The following compounds were prepared with procedures analogous to that described in Example 126 using the specified aryl bromide and boronic acid starting materials:
Figure imgf000166_0001
EXAMPLE 131
3-{[5-(2-chlorophenyl)-1 H-pyrrolo[2,3-(^pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide trifluoroacetate
Figure imgf000167_0001
To a mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-c/]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide (0.100 g, 0.239 mmol), (2-chlorophenyl)boronic acid, and Pd(Ph3)4 (0.1 10 g, 0.096 mmol) in 1 ,4-dioxane (6 mL) was added 0.4 M aq. Na2C03 (2.99 mL, 1 .194 mmol). The mixture was flushed with nitrogen, sealed in a scintillation via\, and heated at 100 °C overnight. The reaction mixture was then quenched with the addition of water and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was dissolved in EtOAc, adsorbed onto silica gel, and purified via flash column chromatography (100% EtOAc). The product containing fractions were concentrated, dissolved in 4 mL of EtOAc-MeOH and further purified via reverse phase HPLC (20-60% CH3CN/water with 0.1 % TFA) to afford the title compound (0.019 g, 15%) as a white solid.
The following compounds were prepared with procedures analogous to that described in Example 131 using 3-[(5-bromo-1 /-/-pyrrolo[2,3-c ] pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide and the specified boronic acid as starting materials:
Figure imgf000167_0002
Figure imgf000168_0001
EXAMPLE 135
3-({5-[4-(aminomethyl)phenyl]-1 H-pyrrolo[2,3-(^pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide
Figure imgf000168_0002
a) 1 ,1 -dimethylethyl 5-bromo-4-[(3-{[{[(1 , 1 -dimethylethyl)oxy]carbonyl}
(methyl)amino]sulfonyl}phenyl)amino]-7H-pyrrolo[2,3-c ]pyrimidine-7-carboxylate
A mixture of the 3-[(5-bromo-1 /-/-pyrrolo[2,3-c/]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide (2 g, 4.78 mmol) in CH3CN (40 mL) was treated with Boc20 (2.44 mL, 10.51 mmol) and DMAP (1 .284 g, 10.51 mmol) and stirred at 25 °C for 1 h. The solvent was removed in vacuo and the residue dissolved in EtOAc, washed with water and brine, dried over Na2S04, filtered, and concentrated. The crude material was purified via flash chromatography (20% EtOAc/hexanes) to afford the title compound (1 .5 g, 53%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H), 8.52 (s, 1 H), 8.35 (s, 1 H), 7.92 (s, 1 H), 7.61 (s, 1 H), 7.64 (s, 1 H), 3.32 (s, 3H), 1.62 (s, 9H), 1.27 (s, 9H); MS (m/z) 582.1 (M+H+). b) 3-({5-[4-(aminomethyl)phenyl]-1 H-pyrro^
methylbenzenesulfonamide
A mixture of 1 , 1-dimethylethyl 5-bromo-4-[(3-{[{[(1 ,1 - dimethylethyl)oxy]carbonyl}(methyl)amino]sulfonyl}phenyl)amino]-7/-/-pyrrolo[2,3- c ]pyrimidine-7-carboxylate (0.150 g, 0.258 mmol), Pd(dppf)CI2 «CH2CI2 (0.075 g, 0.103 mmol), and [4-(aminomethyl)phenyl]boronic acid (0.1 17 g, 0.773 mmol) in 1 ,4-dioxane (5 mL) was treated with 0.4 M aq. Na2C03 (2.58 mL, 1 .030 mmol), purged with nitrogen, and stirred at 100 °C overnight. The mixture was treated with water and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2S04, filtered, and
concentrated in vacuo. The crude material was purified via flash column chromatography (2% MeOH/CH2CI2) and triturated with EtOAc to afford the title compound (0.057 g, 54%) as a tan solid. MS (m/z) 409 (M+H+). The following compounds were prepared with procedures analogous to that described in Example 135 using 1 ,1 -dimethylethyl 5-bromo-4-[(3-{[{[(1 , 1 - dimethylethyl)oxy] carbonyl}(methyl) amino]sulfonyl}phenyl)amino]-7H-pyrrolo[2,3-c/] pyrimidine-7-carboxylate and the specified boronic acid as starting materials:
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
EXAMPLE 151
3-[(5-cyano-1 H-pyrrolo[2,3-(^pyrimidin-4-yl)amino]-/V-methylbenzenesulfon
trifluoroacetate
Figure imgf000171_0002
A mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-c ]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide (0.050 g, 0.131 mmol) and CuCN (0.030 g, 0.335 mmol) in DMF (2 mL) was subjected to microwave irradiation (210 °C) for 60 min. The reaction mixture was then cooled and diluted with CH3CN. The precipitate was removed by filtration and the filtrate was purified via reverse phase HPLC (10-50% CH3CN/water with 0.1 % TFA) to afford the title compound (0.003 g, 5%) as a white solid. MS (m/z) 329 (M+H+). EXAMPLE 152
/V-methyl-3-{[5-(1 -methylethyl)-1 H-pyrrolo[2,3-(^pyrimidin-4-yl]am
hydrochloride
Figure imgf000172_0001
•HCI a) 1 ,1 -dimethylethyl 5-bromo-4-[(3-{[{[(1 , 1 - dimethylethyl)oxy]carbonyl}(methyl)amino]sulfonyl}phenyl)amino]-7/-/-pyrrolo[2,3- c/]pyrimidine-7-carboxylate
A mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-c ]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide (10.0 g, 23.88 mmol) in CH3CN (200 mL) at 25 °C was treated with Boc20 (16.64 mL, 71 .7 mmol) and DMAP (5.84 g, 47.8 mmol) and stirred for 15 min before being concentrated. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2S04, filtered, and concentrated. The crude material was then purified via flash column chromatography (20% EtOAc/hexanes) to afford a yellow solid, which was triturated with EtOAc to afford the title compound (7.5 g, 54%) as a white solid. 1H NMR (400 MHz, DMF) δ ppm 9.23 (s, 1 H), 8.94 (s, 1 H), 8.75 - 8.79 (m, 1 H), 8.45 - 8.51 (m, 1 H), 8.34 (s, 1 H), 7.99 - 8.10 (m, 2H), 3.74 (s, 3H), 2.04 (s, 9H), 1 .69 (s, 9H). b) 1 ,1 -dimethylethyl methyl[(3-{[5-(1-methylethenyl)-1 H-pyrrolo[2,3-c/]pyrimidin-4- yl]amino}phenyl)sulfonyl]carbamate
A mixture of 1 , 1-dimethylethyl 5-bromo-4-[(3-{[{[(1 ,1 - dimethylethyl)oxy]carbonyl}(methyl)amino]sulfonyl}phenyl)amino]-7/-/-pyrrolo[2,3- c/]pyrimidine-7-carboxylate (0.500 g, 0.858 mmol), Pd(dppf)CI2'CH2Cl2 (0.251 g, 0.343 mmol), and isopropenylboronic acid pinacol ester (0.433 g, 2.58 mmol) in 1 ,4-dioxane (12 mL) was treated with 0.4 M aq. Na2C03 (8.58 mL, 3.43 mmol), purged with nitrogen, and stirred at 100 °C for 15 min before being treated with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude material was then purified via flash column chromatography (50% EtOAc/hexanes) to afford the title compound (0.065 g, 17%) as a yellow solid following trituration with MeOH. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (br. s, 1 H), 8.45 (s, 1 H), 8.42 (t, J = 1.88 Hz, 1 H), 8.37 (s, 1 H), 8.01 (dd, J = 1.38, 8.16 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.45 - 7.52 (m, 2H), 5.25 (s, 1 H), 5.06 (s, 1 H), 3.31 (s, 3H), 2.21 (s, 3H), 1 .25 (s, 9H); MS (m/z) 443.9 (M+H+). c) 1 , 1-dimethylethyl methyl[(3-{[5-(1-methylethyl)-1 H-pyrrolo[2,3-c/]pyrimidin-4- yl]amino}phenyl)sulfonyl]carbamate
A solution of 1 , 1-dimethylethyl methyl[(3-{[5-(1-methylethenyl)-1 H-pyrrolo[2,3- c/]pyrimidin-4-yl]amino}phenyl)sulfonyl]carbamate (0.065 g, 0.147 mmol) in MeOH (25 mL) was treated with Pd/C (0.060 g, 0.056 mmol) and stirred at 25 °C under a balloon of H2 overnight. After 16 h, the mixture was filtered and the filtrate was concentrated to afford the title compound (52 mg, 80%) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .67 (br. s, 1 H), 8.45 (br. s, 1 H), 8.32 - 8.36 (m, 1 H), 8.27 (s, 1 H), 8.08 (dd, J = 1.63, 7.65 Hz, 1 H), 7.58 (t, J = 8.03 Hz, 1 H), 7.46 - 7.52 (m, 1 H), 7.08 (s, 1 H), 3.31 (s, 3H), 1 .27 (s, 3H), 1.26 (s, 3H), 1.24 (s, 9H); MS (m/z) 446 (M+H+). d) A/-methyl-3-{[5-(1-methylethyl)-1 H-pyrrolo[2,3-c ]pyrimidin-4- yl]amino}benzenesulfonamide hydrochloride
A mixture of 1 , 1-dimethylethyl methyl[(3-{[5-(1-methylethyl)-1 /-/-pyrrolo[2,3- c/]pyrimidin-4-yl]amino}phenyl)sulfonyl]carbamate (0.052 g, 0.1 17 mmol) in CH3CN (5 mL) at 25 °C was treated with HCI (0.5 mL of a 4 M solution in 1 ,4-dioxane, 2.00 mmol) and stirred overnight before being concentrated to afford an oil. The oil was dissolved in MeOH and filtered, and the filtrate was concentrated to afford the title compound (0.048 mg, 97%) as a pale yellow solid after lyophilization. MS (m/z) 346 (M+H+). EXAMPLE 153
/V-methyl-4-(1-pyrrolidinyl)-3-(1 H-pyrrolo[2,3-(^pyrimidin-4-ylami
Figure imgf000174_0001
A mixture of 4-fluoro-/V-methyl-3-(1 /-/-pyrrolo[2,3-c/]pyrimidin-4- ylamino)benzenesulfonamide (0.045 g, 0.140 mmol) and pyrrolidine (0.5 mL, 6.05 mmol) was stirred at 80 °C overnight before being concentrated. The residue was triturated with EtOAc and dried to afford the title compound (0.024 g, 41 %) as a tan solid. MS (m/z) 373 (M+H+).
EXAMPLE 154
/V-methyl-4-(1 -piperidinyl)-3-(1 H-pyrrolo[2,3-c ]pyrimidin-4-ylamino)benzenesulfonamide trifluoroacetate
Figure imgf000174_0002
•TFA
A mixture of 4-fluoro-/V-methyl-3-(1 /-/-pyrrolo[2,3-c/]pyrimidin-4- ylamino)benzenesulfonamide (0.050 g, 0.156 mmol) in dimethyl sulfoxide (1 mL) was treated with piperidine (0.5 mL, 5.06 mmol) and subjected to microwave irradiation at 150 °C for 30 min before being concentrated, filtered, and purified via reverse phase HPLC (10-50% CHsCN/water with 0.1 %TFA; Sunfire C18 OBD 5 μΜ, 30x75 mm). Lyophilization then afforded the title compound (0.043 g, 54%) as a pale yellow solid. MS (m/z) 387 (M+H+). The following compounds were prepared with procedures analogous to that described in Example 154 using 4-fluoro-/V-methyl-3-(1 /-/-pyrrolo[2,3-c ]pyrimidin-4- ylamino)benzenesulfonamide and the specified amine as starting materials:
Figure imgf000175_0001
Figure imgf000176_0001
EXAMPLE 165
3-[(6-bromo-1 H-pyrrolo[2,3-(^pyrimidin-4-yl)amino]-/V-methylbenzenesulfonam
Figure imgf000176_0002
A suspension of 6-bromo-4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c/]pyrimidine (0.764 g, 2.049 mmol), 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-c/]pyrimidine (0.237 g, 0.807 mmol), A/-methyl-3-aminobenzenesulfonamide (0.532 g, 2.86 mmol), and AgOTf (0.734 g, 2.86 mmol) in isopropanol (8.069 ml.) was heated for 45 min at 120 °C in a microwave reactor. Additional A/-methyl-3-aminobenzenesulfonamide (0.050 g) was added and the mixture returned to the microwave for 30 min at 120 °C. The reaction mixture was then adsorbed onto silica gel and purified via flash column chromatography (0-30% MeOH/CH2CI2) to afford the title compound (0.413 g, 53%) as an off-white solid. MS (m/z) 382, 384 (M+H+). The following compounds were prepared with procedures analogous to that described in Example 165 using the specified chloro-deazapurine and aniline starting materials:
Figure imgf000177_0001
EXAMPLE 172
/V-methyl-3-{[6-(1-pyrrolidinylcarb^
yl]amino}benzenesulfonamide
Figure imgf000178_0001
To a solution of 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 H-pyrrolo[2,3- c ]pyrimidine-6-carboxylic acid (0.035 g, 0.101 mmol) and pyrrolidine (0.025 ml_, 0.302 mmol) in DMF was added PyBOP (0.079 g, 0.151 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with 5 ml. water, the insolubles were collected by filtration, washed with water, and dried to afford the title compound (0.023 g, 57%) as a pale green solid. MS (m/z) 401 (M+H+).
EXAMPLE 173
A/-methyl-3-[(6-phenyl-1 /-/-pyrrolo[2,3-c/]pyrimidin-4-yl)amino]benzenesulfonamide
Figure imgf000178_0002
120 °C, 15 min
An orange suspension of 3-[(6-bromo-1 /-/-pyrrolo[2,3-c ]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide (0.050 g, 0.131 mmol), benzeneboronic acid (0.048 mg, 0.392 mmol), Na2C03 (0.056 g, 0.523 mmol) and Pd(dppf)CI2 «CH2CI2 (0.019 g, 0.026 mmol) in 1 ,4-dioxane (2.355 mL) and water (0.262 mL) was heated to 120 °C for 15 min in a microwave reactor. The reaction mixture was absorbed onto silica gel and purified via flash column chromatography (0-30% MeOH/CH2CI2) to afford the title compound (0.019 g, 38%) as a yellow-green solid. MS (m/z) 380 (M+H+). The following compound was prepared with a procedure analogous to that described in Example 173 using 3-[(6-bromo-1 /-/-pyrrolo[2,3-c ]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide and the specified boronic acid as starting materials:
Figure imgf000179_0001
EXAMPLE 180
/V-methyl-3-{[6-(4-pyridinyl)-1 H-pyrrolo[2,3-(^pyrimidin-4-yl]ami
Figure imgf000180_0001
An orange suspension of 3-[(6-bromo-1 /-/-pyrrolo[2,3-c ]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide (0.075 g, 0.196 mmol), 4-pyridylboronic acid (26.5 mg, 0.216 mmol), Na2C03 (83 mg, 0.785 mmol) and Pd(Ph3)4 (22.67 mg, 0.020 mmol) in 1 ,4-dioxane (3.532 mL) and water (0.392 mL) was heated to 120 °C for 15 min in a microwave reactor. Additional Pd(Ph3)4 (22.67 mg, 0.020 mmol) and 4-pyridylboronic acid (26.5 mg, 0.216 mmol) were added and the mixture was returned to microwave for 15 min at 160 °C. The crude reaction mixture was loaded onto a pre-wetted (MeOH) 20 g SCX cartridge. The non-basic impurities were eluted with MeOH and then 1 N NH3 in MeOH (ca. 100 mL) was used to elute the product. The fractions containing the product were concentrated in vacuo and the residue was stirred with 4 mL CH2CI2 and 1 mL EtOAc. The solids were collected by filtration, washed with CH2CI2 and dried to afford the title compound (0.037 g, 50%) as a brown powder. MS (m/z) 381 (M+H+).
The following compounds were prepared with procedures analogous to that described in Example 180 using 3-[(6-bromo-1 /-/-pyrrolo[2,3-c ]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide and the specified boronic acid as starting materials:
Figure imgf000180_0002
Figure imgf000181_0001
EXAMPLE 188
A/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000181_0002
A mixture of 6-chloropurine (50 mg, 0.324 mmol) and /V-methyl 3- aminobenzenesulfonamide (90 mg, 0.485 mmol) in isopropanol (2 mL) was stirred at 80 °C overnight before being cooled to rt. The solid was collected by filtration, washed with MeOH, and dried to afford the title compound (80 mg, 81 %) as a slightly yellow solid. MS (m/z) 305 (M+H+).
The following compounds were prepared with procedures analogous to that described in Example 188 using the specified aniline and chloro-pyrimidine starting materials: Chloro-
Ex. Name Aniline
Structure pyrimidine
3-amino-A/,4-
A/-4-dimethyl-3-(1 H-purin-6-
189 dimethylbenz ylamino)benzenesulfonamid purine
enesulfonami e trifluoroacetate Λ Sj Λ 0 6-chloro
de
A/-methyl-3-(1 H-
4-chloro-1 /-/- /V-methyl 3-
190 py razolo[3 ,4-d] py rim id in-4- pyrazolo[3,4- aminobenzen ylamino)benzenesulfonamid
Figure imgf000182_0001
cfjpyrimidine esulfonamide e trifluoroacetate
EXAMPLE 191
4-(dimethylamino)-/V-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide trifluoroacetate
Figure imgf000182_0002
A mixture of 6-chloro-7-methyl-7-deazapurine (50 mg, 0.298 mmol) and 3-amino-4- (dimethylamino)-/V-methylbenzenesulfonamide (82 mg, 0.358 mmol) in isopropanol (2 mL) was treated with 1 M aq. HCI (0.298 mL, 0.298 mmol) and subjected to microwave irradiation at 150 °C for 30 min before being filtered and subjected to reverse phase HPLC (10-40% CH3CN/water with 0.1 %TFA; Sunfire C18 OBD 5 μΜ, 30x75 mm) to afford a yellow oil, which was dissolved in water and lyophilized to afford the title compound (28 mg, 19.6%) as an orange solid. MS (m/z) 361 (M+H+).
The following compounds were prepared with procedures analogous to that described in Example 191 using the indicated chloro-deazapurine and aniline starting materials:
Figure imgf000183_0001
Figure imgf000184_0001
A/-methyl-4- 3-amino-/V-
(propylamino)-3-(1 /-/- methyl-4-
206 6-chloro-7- pyrrolo[2,3-d]pyrimidin-4- (propylamino) deazapurine
ylamino)benzenesulfona benzenesulfon
Figure imgf000185_0001
mide amide
EXAMPLE 207
/V-methyl-2-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-biphenylsulfonami trifluoroacetate
Figure imgf000185_0002
a) 4-chloro-/V-methyl-3-(1 H-pyrrolo[2,3-(^pyrimidin-4-ylamino)benzenesulfonami A solution of 3-amino-4-chloro-/V-methylbenzenesulfonamide (0.826 g, 3.74 mmol) and 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (1 g, 3.40 mmol) in NMP (20 mL) was treated with AgOTf (0.875 g, 3.40 mmol) and heated at 165 °C for 60 h before being cooled and partitioned between 250 mL EtOAc and 30 mL water. The organic layer was washed with brine (20 mL x 2), dried over MgS04, concentrated, and purified by flash column chromatography (0-10% MeOH/CH2CI2) to afford the title compound (315 mg,
23%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .84 (br. s, 1 H), 9.29 (s, 1 H), 8.19 (s, 1 H), 8.10 - 8.17 (m, 1 H), 7.80 (d, J=8.28 Hz, 1 H), 7.57 - 7.63 (m, 2 H), 7.24 - 7.32 (m, 1 H), 6.66 (br. s, 1 H), 2.48 (d, J=4.52 Hz, 3 H). MS (m/z) 338.1 (M+H+). b) A/-methyl-2-(1 /-/-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-biphenylsulfonamide
trifluoroacetate
A mixture of 4-chloro-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide (70 mg, 0.207 mmol) and phenylboronic acid (37.9 mg, 0.31 1 mmol) in 1 ,4-dioxane (4 mL) and water (1 mL) was treated with K2C03 (57.3 mg, 0.414 mmol) and PdCI2(dppf CH2Cl2 (16.92 mg, 0.021 mmol) and heated at 140 °C for 4 h before being concentrated and subjected to reverse phase HPLC to afford the title compound (41 mg, 38%). MS (m/z) 380 (M+H+).
The following compounds were prepared with procedures analogous to that described in Example 207 using the indicated chloro-deazapurine in step 1 and the indicated boronic acid in step 2:
Figure imgf000186_0001
EXAMPLE 21 1
/V-methyl-3-{[5-(2-methylpropyl)-1 H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide trifluoroacetate
Figure imgf000187_0001
a) /V-methyl-3-{[5-(2-methyl-2-propen-1-yl)-1 H-pyrrolo[2,3-c/]pyrimidin-4- yl]amino}benzenesulfonamide A mixture of 4-chloro-5-(2-methyl-2-propen-1 -yl)-7H-pyrrolo[2,3-c ]pyrimidine (100 mg, 0.483 mmol) and 3-amino-/V-methylbenzenesulfonamide (135 mg, 0.726 mmol) in DMF (5 mL) was treated with AgOTf (124 mg, 0.483 mmol) and heated at 80 °C for 10 h before being cooled and partitioned between water and CH2CI2 (3 x 10 mL). The combined organic extracts were dried (Na2S04) and concentrated to afford the title compound (150 mg, 87%) as a black oil. MS (m/z) 358 (M+H+). b) A/-methyl-3-{[5-(2-methylpropyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide trifluoroacetate A solution of A/-methyl-3-{[5-(2-methyl-2-propen-1-yl)-1 /-/-pyrrolo[2,3-c/]pyrimidin-4- yl]amino}benzenesulfonamide (150 mg, 0.42 mmol) in MeOH (20 mL) was treated with Pd/C (100 mg) and stirred at rt under 30 psi of H2 for 16 h before being filtered, concentrated, and subjected to reverse phase HPLC to afford the title compound (24 mg, 16%) as a brown solid. MS (m/z) 360 (M+H+). EXAMPLE 212
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/V-methyl-4-(4- piperidinyl)benzenesulfonamide
Figure imgf000188_0001
To a solution of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (4-methyl-1 -piperidinyl)benzenesulfonamide (200mg, 0.416 mmol), 2-(3-furanyl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane (121 mg, 0.63 mmol) and K2C03 (288 mg, 2.08 mmol) in 1 ,4-dioxane (5 ml.) and water (1 mL) was added PdCI2(dppf)«CH2CI2 (34 mg, 0.04 mmol). The reaction vessel was sealed and heated at 150 °C for 40 min. The reaction mixture was concentrated onto silica gel and purified by flash column chromatography (0-6% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford a light yellow solid which was triturated with hot CH2CI2 to afford the title compound (55.8 mg, 27%) as a white solid. LCMS (ES) m/z 468 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.73 - 0.82 (m, 2 H) 0.86 (d,
J=6.57 Hz, 3 H) 1 .34 (br. s, 1 H) 1 .49 (br. s, 2 H) 2.47 - 2.49 (m, 3 H) 2.53 - 2.61 (m, 2 H) 2.86 (d, J=1 1 .37 Hz, 2 H) 6.96 (s, 1 H) 7.36 (d, J=8.34 Hz, 1 H) 7.44 - 7.52 (m, 2 H) 7.98 (t, J=1 .64 Hz, 1 H) 8.33 (s, 1 H) 8.46 (s, 1 H) 8.52 (s, 1 H) 9.03 (d, J=2.02 Hz, 1 H) 13.97 (s, 1 H).
EXAMPLE 213
3-{[3-(3-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-{4- [(methyloxy)methyl]-1 -piperidinyl}benzenesulfonamide
Figure imgf000188_0002
To a solution of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- {4-[(methyloxy)methyl]-1-piperidinyl}benzenesulfonamide (160 mg, 0.31 mmol) and 2-(3- furanyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (72.9 mg, 0.376 mmol) in 1 ,4-dioxane (2.0 mL) and water (0.5 mL) were added K2C03 (130 mg, 0.939 mmol) and
PdCI2(dppf)«CH2Ci2 (25.6 mg, 0.031 mmol) . The reaction vessel was sealed, heated at 150 °C for 40 min, and concentrated. The residue was purified by flash column chromatography (3-7% MeOH/CHCI3) to afford a light yellow solid. The solid was washed with hot CH2CI2 to afford the title compound (52.4 mg, 34%) as a white solid. LCMS (ES) m/z 498 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (br. s, 2 H) 1.57 (br. s, 3 H) 2.48 (d, J=5.05 Hz, 3 H) 2.55 (br. s, 2 H) 2.90 (br. s, 2 H) 3.10 (d, J=6.32 Hz, 2 H) 3.23 - 3.31 (m, 3 H) 6.96 (s, 1 H) 7.34 - 7.42 (m, 1 H) 7.43 - 7.53 (m, 2 H) 7.99 (d, J=1 .26 Hz, 1 H) 8.33 (s, 1 H) 8.45 (s, 1 H) 8.51 (s, 1 H) 9.03 (d, J=2.02 Hz, 1 H) 13.97 (br. s, 1 H).
EXAMPLE 214
3-{[3-(3-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(4-hydroxy-1-piperidinyl)-/\/- methylbenzenesulfonamide
Figure imgf000189_0001
To a solution of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(4-hydroxy- 1-piperidinyl)-/V-methylbenzenesulfonamide (145 mg, 0.30 mmol) and 2-(3-furanyl)- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (61 mg, 0.31 mmol) in 1 ,4-dioxane (3.0 mL) and water (0.5 mL) was added K2C03 (125 mg, 0.90 mmol) and PdCI2(dppf CH2Cl2 (24.55 mg, 0.03 mmol) . The reaction vessel was sealed, heated at 150 °C for 40 min, and concentrated. The residue was purified by flash column chromatography (3-7%
MeOH/CHCIs) to afford the title compound (42.6 mg, 29%) as a light yellow solid. LCMS (ES) m/z 470 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=4.29 Hz, 2 H) 1.49 (br. s, 2 H) 2.48 (d, J=5.05 Hz, 3 H) 2.59 (d, J=8.34 Hz, 3 H) 2.88 (br. s, 2 H) 4.58 (d, J=3.03 Hz, 1 H) 6.93 (s, 1 H) 7.34 - 7.43 (m, 1 H) 7.44 - 7.53 (m, 2 H) 7.92 (d, J=1.26 Hz, 1 H) 8.32 (s, 1 H) 8.45 - 8.56 (m, 2 H) 9.02 (d, J=2.02 Hz, 1 H) 13.97 (s, 1 H). EXAMPLE 215
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(3-hydroxy-1-pipen
methylbenzenesulfonamide
Figure imgf000190_0001
To a solution of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(3-hydroxy- 1-piperidinyl)-/V-methylbenzenesulfonamide (100 mg, 0.207 mmol) and 2-(2-furanyl)- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (42.2 mg, 0.218 mmol) in 1 ,4-dioxane (2.0 mL) and water (0.5 mL) were added K2C03 (86 mg, 0.62 mmol) and PdCI2(dppf)«CH2Cl2 (16.9 mg, 0.02 mmol) . The reaction vessel was sealed, heated at 150 °C for 40 min, and concentrated. The residue was purified by flash column chromatography (3-7%
MeOH/CHCIs) to afford the title compound (21 .7 mg, 21 %) as a tan solid. LCMS (ES) m/z 470 (M+H)+; 1H N MR (400 MHz, DMSO-d6) δ ppm 1 .14 (br. s, 1 H) 1 .29 (d, J=13.89 Hz, 2 H) 1 .64 (br. s, 1 H) 1 .76 (br. s, 1 H) 2.28 - .37 (m, 1 H) 2.46 (d, J=4.80 Hz, 3 H) 2.67 (br. s, 1 H) 3.00 (br. s, 1 H) 3.15 (br. s, 1 H) 4.74 (d, J=4.55 Hz, 1 H) 6.77 - 6.86 (m, 1 H) 7.09 (d, J=3.28 Hz, 1 H) 7.35 (d, J=8.34 Hz, 1 H) 7.39 - 7.44 (m, 1 H) 7.53 (dd, J=8.46, 2.15 Hz, 1 H) 7.99 (s, 1 H) 8.45 (s, 1 H) 8.59 (d, J=2.02 Hz, 1 H) 9.05 (s, 1 H) 14.08 (s, 1 H). EXAMPLE 216
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[4-(trifluoromethyl)-1- piperidinyl]benzenesulfonamide
Figure imgf000190_0002
To a solution of 3-amino-/V-methyl-4-[4-(trifluoromethyl)-1- piperidinyl]benzenesulfonamide (150 mg, 0.44 mmol) and 3-bromo-4-chloro-1 /-/- pyrazolo[3,4-d]pyrimidine (103 mg, 0.44 mmol) in 1 ,4-dioxane (5 ml.) was added AgOTf (341 mg, 1.33 mmol). The reaction vessel was sealed and heated at 90 °C for 20 h. The reaction mixture was concentrated and purified by flash column chromatography (1 -7% MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (92.1 mg, 37%) as an off-white solid. LCMS (ES) m/z 535 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.87 (td, J=12.13, 3.54 Hz, 2 H) 1 .92 - 2.02 (m, 2 H) 2.46 (d, J=5.05 Hz, 3 H) 2.79 - 2.90 (m, 2 H) 3.1 1 - 3.19 (m, 2 H) 3.57 (s, 1 H) 7.46 - 7.51 (m, 1 H) 7.51 - 7.58 (m, 2 H) 8.55 (s, 1 H) 9.06 (d, J=1 .77 Hz, 1 H) 9.15 (s, 1 H) 14.26 (br. s, 1 H).
EXAMPLE 217
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-{4-[(methyloxy)methyl]-1 - piperidinyl}benzenesulfonamide
Figure imgf000191_0001
To a solution of 3-amino-/V-methyl-4-{4-[(methyloxy)methyl]-1-piperidinyl}-1 ,5- cyclohexadiene-1 -sulfonamide (160 mg, 0.507 mmol) and 3-bromo-4-chloro-1 /-/- pyrazolo[3,4-d]pyrimidine (124 mg, 0.53 mmol) in 1 ,4-dioxane (5 ml.) was added AgOTf (195 mg, 0.76 mmol). The reaction vessel was sealed and heated at 90 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (1 -7%
MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (54.2 mg, 20%) as a light yellow solid. LCMS (ES) m/z 51 1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .64 (br. s, 2 H) 1 .76 (br. s, 3 H) 2.46 (d, J=5.05 Hz, 3 H) 2.71 - 2.81 (m, 2 H) 3.05 (d, J=10.61 Hz, 2 H) 3.26 - 3.31 (m, 5 H) 7.47 (t, J=4.80 Hz, 1 H) 7.52 (s, 2 H) 8.48 - 8.61 (m, 1 H) 9.10 (s, 1 H) 9.23 (s, 1 H) 14.23 (br. s, 1 H). EXAMPLE 218
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/V-methyl-4-[4-(m
piperidinyl]benzenesulfonamide
Figure imgf000192_0001
To a solution of 3-amino-/V-methyl-4-[4-(methyloxy)-1-piperidinyl]-1 ,5- cyclohexadiene-1 -sulfonamide (1 10 mg, 0.365 mmol) and 3-bromo-4-chloro-1 /-/- pyrazolo[3,4-d]pyrimidine (89 mg, 0.38 mmol) in 1 ,4-dioxane (4 mL) was added AgOTf (281 mg, 1.09 mmol). The reaction vessel was sealed and heated at 90 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (1 -7%
MeOH/CHCIs containing 0.1 % ΝΗ3·Η20) to afford the title compound (57 mg, 30%) as a light yellow solid. LCMS (ES) m/z 497 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.75 (br. s, 2 H) 2.03 (br. s, 2 H) 2.45 (s, 3 H) 2.80 (br. s, 2 H) 3.03 (br. s, 2 H) 3.29 (s, 4 H) 7.45 (s, 1 H) 7.52 (s, 2 H) 8.53 (s, 1 H) 9.04 (s, 1 H) 9.14 (s, 1 H) 14.22 (br s, 1 H).
EXAMPLE 219
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4-methyl-1 - piperidinyl)benzenesulfonamide
Figure imgf000192_0002
To a solution of 3-amino-/V-methyl-4-(4-methyl-1-piperidinyl)benzenesulfonamide (1 10 mg, 0.38 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (94 mg, 0.40 mmol) in 1 ,4-dioxane (4 mL) was added AgOTf (149 mg, 0.58 mmol). The reaction vessel was sealed and heated at 90 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (1-7% MeOH/CHCI3 containing 0.1 % ΝΗ3·Η20) to afford the title compound (41 .3 mg, 21 %) as a white solid. LCMS (ES) m/z 481 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J=5.31 Hz, 3 H) 1 .54 (d, J=7.07 Hz, 3 H) 1.75 (d, J=9.85 Hz, 2 H) 2.46 (d, J=5.05 Hz, 3 H) 2.71 - 2.82 (m, 2 H) 3.03 (d, J=1 1 .37 Hz, 2 H) 7.46 (t, J=5.05 Hz, 1 H) 7.50 - 7.56 (m, 2 H) 8.53 (s, 1 H) 9.03 (s, 1 H) 9.15 (s, 1 H) 14.24 (br. s, 1 H).
EXAMPLE 220
/V-methyl-4-({[3-(methyloxy)phenyl]methyl}amino)-3-(1 H-purin-6- ylamino)benzenesulfonamide
Figure imgf000193_0001
A mixture of 4-fluoro-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide (0.3 g, 0.93 mmol) and 1 -[3-(methyloxy)phenyl]methanamine (0.192 g, 1 .40 mmol) in NMP (2.33 mL) was stirred at 100 °C in a sealed high pressure vessel for 18 h. The reaction mixture was dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-10% of a 90:9:0.9 solution of CHCI3:MeOH:NH4OH in CHCI3. The desired fractions were combined and concentrated in vacuo. The residue was taken into a small amount of MeOH and crashed out of solution using CH2CI2. This resulting off-white precipitate was collected by filtration and dried in vacuo to afford the title compound as an off-white solid (148 mg, 36%). LCMS (ES) m/e 440.1 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm
2.37 (3 H, d, J=5.05 Hz) 3.69 (3 H, s) 4.36 (2 H, d, J=5.56 Hz) 6.51 (1 H, br. s) 6.59 (1 H, d, J=8.59 Hz) 6.73 - 6.85 (1 H, m) 6.90 - 7.12 (3 H, m) 7.23 (1 H, t, J=7.96 Hz) 7.37 (1 H, dd) 7.46 - 7.65 (1 H, m) 8.23 (2 H, d, J=7.83 Hz) 9.21 (1 H, br. s) 13.02 (1 H, br. s).
EXAMPLE 221
/V-methyl-4-({[3-(methyloxy)phenyl]methyl}oxy)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
Figure imgf000194_0001
To a solution of [3-(methyloxy)phenyl]methanol (0.771 mL, 6.21 mmol) in NMP (1 .55 mL) was added 60% NaH in mineral oil (0.248 g, 6.21 mmol). The reaction mixture was stirred for 15 min and purged with nitrogen during gas evolution. A solution of 4- fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (0.2 g, 0.621 mmol) in NMP (1 .551 mL) was added and the reaction mixture stirred at 120 °C in a sealed high pressure vessel for 18 h. The reaction mixture was dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-10% of a 90:9.1 solution of CHCl3:MeOH:NH4OH in CHCI3. The desired fractions were combined and concentrated in vacuo. The residue was triturated with MeOH and a CHCI3/CH2CI2 mixture to crash out the title compound as an off-white solid. This precipitate was collected by filtration and dried in vacuo to afford the title compound (82 mg, 30%) as an off-white solid. LCMS (ES) m/e 441 .1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (3 H, d, J=5.05 Hz) 3.75 (3 H, s) 5.32 (2 H, s) 6.91 (1 H, dd, J=7.96, 2.15 Hz) 7.03 (1 H, d, J=7.58 Hz) 7.07 (1 H, s) 7.31 (1 H, t, J=7.83 Hz) 7.34 - 7.43 (2 H, m) 7.50 (1 H, dd, J=8.59, 2.27 Hz) 8.30 (1 H, s) 8.45 (1 H, s) 8.71 (1 H, s) 8.88 (1 H, d, J=2.02 Hz) 13.27 (1 H, br. s).
EXAMPLE 222
A/-methyl-4-(methyl{[3-(methyloxy)phenyl]methyl}amino)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide
Figure imgf000194_0002
A mixture of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (0.3 g, 0.931 mmol) and A/-methyl-1 -[3-(methyloxy)phenyl]methanamine (0.704 g, 4.65 mmol) in NMP (2.327 mL) was stirred at 120 °C in a sealed high pressure vessel for 3 d. The reaction mixture was dry loaded onto silica gel and purified by flash column
chromatography, eluting with 0-100% of a 90:9:0.9 solution of CHCl3:MeOH:NH4OH in CHCI3. The desired fractions were combined and concentrated in vacuo. The residue was taken into a small amount of MeOH and crashed out of solution using CHCI3. This resulting off-white precipitate was collected by filtration and dried in vacuo to afford the title compound (120 mg, 28%) as an off-white solid. LCMS (ES) m/e 454.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (3 H, d, J=5.05 Hz) 2.65 (4 H, s) 3.71 (3 H, s) 4.12 (2 H, s) 6.78 (1 H, dd, J=8.21 , 1.89 Hz) 6.91 - 7.01 (2 H, m) 7.18 (1 H, t, J=7.83 Hz) 7.36 - 7.52 (3 H, m) 8.28 - 8.37 (2 H, m) 8.47 (1 H, s) 8.94 (1 H, br. s) 9.21 (1 H, s) 13.17 (1 H, br. s). EXAMPLE 223
A/-methyl-4-(2-methyl-1-pyrrolidinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide
Figure imgf000195_0001
A mixture of 4-fluoro-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide (0.2 g,
0.621 mmol) and 2-methylpyrrolidine (0.264 g, 3.10 mmol) in NMP (1.551 mL) was stirred at 120 °C in a sealed high pressure vessel for 5 d. The reaction mixture was dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-80% of a 90:9:1 solution of CHCI3:MeOH:NH4OH in CHCI3. The desired fractions were combined and concentrated in vacuo. The residue was taken into a small amount of MeOH and crashed out of solution using CH2CI2. The resulting precipitate was collected by filtration and dried in vacuo to afford the title compound (22 mg, 9%) as an off-white solid. LCMS (ES) m/e 388.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (3 H, d, J=5.81 Hz) 1.42 - 1.57 (1 H, m) 1.65 - 1 .79 (1 H, m) 1 .81 - 1 .93 (1 H, m) 2.04 - 2.17 (1 H, m) 2.43 (3 H, d, J=5.05 Hz) 2.96 - 3.08 (1 H, m) 3.42 - 3.54 (1 H, m) 3.74 - 3.90 (1 H, m) 7.13 (1 H, d, J=8.59 Hz) 7.23 (1 H, q, J=5.05 Hz) 7.45 (1 H, dd, J=8.59, 2.27 Hz) 8.16 (1 H, br. s) 8.24 (1 H, s) 8.31 (1 H, s) 9.07 (1 H, br. s) 13.13 (1 H, br. s). EXAMPLE 224
4-[[(3-hydroxyphenyl)methyl](methyl)amino]-/V-methyl-3-(1 H-purin-6- ylamino)benzenesulfonamide
Figure imgf000196_0001
A mixture of 4-fluoro-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide (0.3 g, 0.931 mmol) and 3-[(methylamino)methyl]phenol (0.638 g, 4.65 mmol) in NMP (2.327 mL) was stirred at 120 °C in a sealed high pressure vessel for 3 d. The reaction mixture was dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-60% of a 90:9:1 solution of CHCl3:MeOH:NH4OH in CHCI3. The desired fractions were combined and concentrated in vacuo. The residue was further purified by reverse phase HPLC, eluting with CH3CN/water each containing 0.1 % TFA. The cleanest desired fractions were combined, neutralized with 2 M NH3 in MeOH and concentrated in vacuo. The residue was filtered through a plug of silica eluting with 90:9:1 solution of
CHCI3:MeOH:NH4OH and concentrated in vacuo to afford the title compound (22 mg, 5.4%) as a yellow solid. LCMS (ES) m/e 440.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (3 H, d, J=5.05 Hz) 2.66 (3 H, s) 4.08 (2 H, s) 6.61 (1 H, dd, J=8.08, 1.77 Hz) 6.69 (1 H, s) 6.85 (1 H, d, J=7.33 Hz) 7.00 - 7.1 1 (1 H, m) 7.39 (1 H, q, J=5.05 Hz) 7.43 (2 H, s) 8.27 - 8.38 (1 H, m) 8.47 (1 H, s) 8.92 (1 H, br. s) 9.13 (1 H, s) 9.30 (1 H, br. s) 13.20 (1 H, br. s).
EXAMPLE 225
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-c ]pyrimidin-4-yl]amino}-4-(3-hydroxy-1 -piperidinyl)-/\/- methylbenzenesulfonamide
Figure imgf000196_0002
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(3-hydroxy-1- piperidinyl)-/V-methylbenzenesulfonamide (78 mg, 0.162 mmol), 3-furanylboronic acid (90 mg, 0.809 mmol), PdCI2(dppf CH2Cl2 (13.21 mg, 0.016 mmol) and 2 M aq. K2C03 (404 μΙ_, 0.81 mmol) in 1 ,4-dioxane (1.08 mL) was stirred for 40 min at 150 °C under microwave irradiation. The organic layer was separated, concentrated onto Celite®, and dry loaded onto a silica column. Purification was accomplished by flash column chromatography using 30-80% of a 1 :9:90 NH4OH:MeOH:CI-ICl3 solution in CHCI3 as eluent. The desired fractions were combined and concentrated in vacuo. The residue was triturated with CH2CI2 and the solid was collected by filtration and dried in vacuo to afford the title compound (58 mg, 76%) as an off-white solid. LCMS (ES) m/e 470.2 (M+H)+; 1 H NMR (400 MHz, DMSO-de) δ ppm 0.97 - 1 .19 (2 H, m) 1.47 - 1.64 (1 H, m) 1.67 - 1.85 (1 H, m) 2.26 (1 H, t, J=10.1 1 Hz) 2.39 - 2.46 (1 H, m) 2.48 (3 H, d, J=5.05 Hz) 2.74 - 2.85 (1 H, m) 2.86 - 2.98 (1 H, m) 3.05 - 3.15 (1 H, m) 4.74 (1 H, d, J=4.55 Hz) 6.94 (1 H, s) 7.36 (1 H, d, J=8.34 Hz) 7.41 - 7.52 (2 H, m) 7.95 (1 H, s) 8.32 (1 H, s) 8.36 - 8.45 (1 H, m) 8.49 - 8.58 (1 H, m) 9.00 (1 H, d, J=2.02 Hz) 13.97 (1 H, br. s).
EXAMPLE 226
3-[(3-bromo-1 /-/-pyrazolo[3,4-c/]pyrimidin-4-yl)amino]-/\/-methyl-4-(2-methyl-1 - pyrrolidinyl)benzenesulfonamide
Figure imgf000197_0001
a) A/-methyl-4-(2-methyl-1-pyrrolidinyl -3-nitrobenzenesulfonamide
Figure imgf000197_0002
To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (1 g, 4.27 mmol) in 1 ,4-dioxane (21.35 mL) at rt was added 2-methylpyrrolidine (1 .091 g, 12.81 mmol). The reaction mixture was then heated at 100 °C for 18 h. The reaction mixture was concentrated in vacuo to afford a bright yellow oil which was purified by flash column chromatography (30-50% EtOAc/hexanes). The desired fractions were combined and concentrated in vacuo to afford the title compound (1 .24 g, 97%) as a bright yellow solid. LCMS (ES) m/e 300.0 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (3 H, d, J=6.06 Hz) 1.57 - 1.80 (2 H, m) 1 .88 - 2.05 (1 H, m) 2.18 - 2.32 (1 H, m) 2.41 (3 H, s) 2.64 - 2.79 (1 H, m) 3.39 (1 H, td, J=10.42, 6.19 Hz) 3.97 - 4.16 (1 H, m) 7.30 (1 H, d, J=9.09 Hz) 7.40 (1 H, br. s) 7.74 (1 H, dd, J=9.09, 2.27 Hz) 8.10 (1 H, d, J=2.27 Hz). b) 3-amino-/V-methyl-4-(2-methyl-1-p rrolidinyl)benzenesulfonamide
Figure imgf000198_0001
To a suspension of 10% Pd/C (0.444 g, 0.418 mmol) in EtOH (10.4 ml.) in a Parr bottle at rt was added A/-methyl-4-(2-methyl-1-pyrrolidinyl)-3-nitrobenzenesulfonamide (1 .25 g, 4.18 mmol) in EtOH (10.4 ml_). The reaction mixture was stirred for 1 h at rt under 35 psi of H2 gas. The reaction mixture was filtered through Celite® and then through a 0.2 mm acrodisc filter. The filtrate was concentrated in vacuo to afford a brown solid. This material was dissolved in CHCI3 and purified by flash column chromatography, eluting with 50% of a 90:9:1 CHCI3:MeOH:NH4OH solution in CHCI3. The desired fractions were combined and concentrated in vacuo to afford the title compound (0.97 g, 86%) as a bright yellow solid. LCMS (ES) m/e 270.0 (M+H)+; 1H NMR (400 MHz, DMSO- d6) δ ppm 0.91 (3 H, d, J=6.06 Hz) 1.41 - 1.55 (1 H, m) 1.67 - 1.81 (1 H, m) 1 .83 - 1.96 (1 H, m) 2.07 - 2.18 (1 H, m) 2.38 (3 H, d, J=4.80 Hz) 2.53 - 2.59 (1 H, m) 3.54 - 3.70 (2 H, m) 5.03 (2 H, s) 6.89 - 6.99 (2 H, m) 7.02 - 7.1 1 (2 H, m). c) 3-[(3-bromo-1 H-pyrazolo[3,4-c/]pyrimidin-4-yl)amino]-/\/-methyl-4-(2-methyl-1 - pyrrolidinyl)benzenesulfonamide
Figure imgf000198_0002
A heterogeneous mixture of 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (0.4 g, 1.713 mmol), 3-amino-/V-methyl-4-(2-methyl-1-pyrrolidinyl)benzenesulfonamide (0.462 g, 1.713 mmol), and AgOTf (0.528 g, 2.056 mmol) in 1 ,4-dioxane (4.28 mL) was stirred at 100 °C in a sealed high pressure vessel for 72 h. The reaction mixture was concentrated onto silica gel and the material dry-loaded onto a silica column. This material was purified by flash column chromatography, eluting with 0-100% of a 90:9:1 solution of
CHCl3:MeOH:NH4OH in CHCI3. The desired fractions were concentrated in vacuo to afford the title compound as a grey solid. The solid was dissolved into MeOH, filtered through an acrodisc (2 μΜ) and crashed out with CH2CI2. The resulting solid was collected by filtration to afford the title compound (158 mg, 19.8%) as an off-white solid. LCMS (ES) m/e 466.1 , 468.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (3 H, d, J=5.81 Hz) 1.51 - 1.68 (1 H, m) 1.75 - 1.90 (1 H, m) 1.91 - 2.05 (1 H, m) 2.08 - 2.23 (1 H, m) 2.46 (3 H, d, J=5.05 Hz) 2.80 - 2.94 (1 H, m) 3.41 - 3.55 (1 H, m) 3.60 - 3.75 (1 H, m) 7.33 - 7.47 (2 H, m) 7.47 - 7.56 (1 H, m) 8.48 (1 H, s) 8.82 (1 H, s) 9.24 (1 H, s) 14.17 (1 H, br. s).
EXAMPLE 227
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-c/]pyrimidin-4-yl]amino}-/\/-methyl-4-(2-methyl-1 - pyrrolidinyl)benzenesulfonamide
Figure imgf000199_0001
A mixture of 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(2- methyl-1 -pyrrolidinyl)benzenesulfonamide (80 mg, 0.172 mmol), 3-furanylboronic acid (96 mg, 0.858 mmol), PdCI2(dppf)«CH2CI2 (14.01 mg, 0.017 mmol) and 2 M aq. K2C03 (0.43 ml_, 0.858 mmol) in 1 ,4-dioxane (1 .1 ml.) was stirred for 40 min at 150 °C under microwave irradiation. The organic layer was separated, concentrated onto Celite®, and dry loaded onto a silica column. Purification by flash column chromatography using 30- 80% of a 1 :9:90 NH4OH:MeOH:CHCI3 solution in CHCI3 as eluent provided clean fractions of title compound. These fractions were combined and concentrated in vacuo. The resulting residue was triturated with CH2CI2 and the solid was collected by filtration and dried in vacuo to afford the title compound (25 mg, 32%) as an off-white solid. LCMS (ES) m/e 454.0 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (3 H, d, J=6.06 Hz) 1.19 - 1.38 (1 H, m) 1 .51 - 1.76 (2 H, m) 1 .91 - 2.05 (1 H, m) 2.44 - 2.49 (3 H, m) 2.58 - 2.71 (1 H, m) 3.08 - 3.26 (1 H, m) 3.39 - 3.51 (1 H, m) 6.88 - 6.95 (1 H, m) 7.35 (1 H, d, J=8.34 Hz) 7.40 (1 H, q, J=4.97 Hz) 7.46 (1 H, dd, J=8.34, 2.02 Hz) 7.98 (1 H, s) 8.28 (1 H, s) 8.50 (2 H, s) 8.96 (1 H, d, J=2.02 Hz) 13.94 (1 H, br. s).
EXAMPLE 228
3-[(3-bromo-1 H-pyrazolo[3,4-(^pyrimidin-4-yl)amino]-4-[ethyl(methyl)am
methylbenzenesulfonamide
Figure imgf000200_0001
A heterogeneous mixture of 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (329 mg, 1 .41 mmol), 3-amino-4-[ethyl(methyl)amino]-/\/-methylbenzenesulfonamide (343 mg, 1.41 mmol), and AgOTf (435 mg, 1.69 mmol) in 1 ,4-dioxane (3.5 mL) was stirred at 100 °C in a sealed high pressure vessel for 72 h. The reaction mixture was concentrated onto silica gel and the material dry-loaded onto a silica column. This material was purified by flash column chromatography, eluting with 0-100% of a 90:9:1 solution of
CHCI3:MeOH:NH4OH in CHCI3. The desired fractions were concentrated in vacuo to afford the title compound as an off-white solid. The solid was further purified by flash column chromatography, eluting with 10-30% of a 90:9:1 solution of CHCI3:MeOH:NH4OH in CHCI3. The desired fractions were combined, concentrated in vacuo, and the solid was triturated with CH2CI2. The resulting solid was collected and dried in vacuo to afford the title compound (1 12 mg, 18%) as an off-white solid. LCMS (ES) m/e 440.1 , 442.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .04 (3 H, t, J=7.07 Hz) 2.47 (3 H, d, J=4.80 Hz) 2.71 (3 H, s) 3.07 (2 H, q, J=7.07 Hz) 7.47 (1 H, q, J=4.97 Hz) 7.50 - 7.57 (2 H, m) 8.55 (1 H, s) 9.20 (1 H, d, J=1 .77 Hz) 9.66 (1 H, s) 14.20 (1 H, br. s).
EXAMPLE 229
/V-methyl-4-[(2S)-2-methyl-1-pyrrolidinyl]-3-[(5-methyl-1 H-pyrrolo[2,3-d
yl)amino]benzenesulfonamide
Figure imgf000201_0001
A mixture of 4-chloro-7-methyl-7-deazapurine (32 mg, 0.191 mmol) and 3-amino- A/-methyl-4-[(2S)-2-methyl-1-pyrrolidinyl]benzenesulfonamide (77 mg, 0.286 mmol) in /'- PrOH (2 mL) was treated with 1 M aqueous HCI (0.191 mL, 0.191 mmol) and subjected to microwave irradiation (150 °C, 10 bar) for 60 minutes before being filtered and subjected to reverse phase HPLC (30-80% MeCN/aq. NH4OH pH 10, XBridge C18 OBD 30x150 mm) to give A/-methyl-4-[(2S)-2-methyl-1-pyrrolidinyl]-3-[(5-methyl-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl)amino]benzenesulfonamide (8.5 mg, 10%) as a tan solid. The following compounds were prepared with procedures analogous to that described in Example 229 using the specified chloro-deazapurine and aniline starting materials:
Figure imgf000201_0002
Figure imgf000202_0001
Figure imgf000203_0001
Spectroscopic data for Examples 101-211 and 229-241:
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
trifluoroacetate
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
a LCMS Method: Agilent 1100 Series LC/MSD SL or VL using electrospray positive [ES+ve to afford M+H+] equipped with a Sunfire C18 5.0 μιη column (3.0 mm x 50 mm, i.d.), eluting with 0.05% TFA in water (solvent A) and 0.05% TFA in CH3CN (solvent B), using the following elution gradient: 10-100% (solvent B) over 2.5 min and holding at 100% for 1.7 min at a flow rate of 1.0 mL/min. b LCMS Method: Agilent 1100 Series LC/MSD SL or VL using electrospray positive [ES+ve to affordM+H+] equipped with a XBridge C18 100 x 4.6mm column (3.5 μΐη particle size), eluting with 10 mM NH4HCO3 in water (solvent A) and CH3CN (solvent B) linear gradient from 5-95% over 10 min, 1.2 mL/min flow rate. c LCMS Method: Agilent 1200 Series LC/MSD VL using electrospray positive [ES+ve to affordM+H+] equipped with a shim-pack XR-ODS 2.2 μΐη column (3.0 mm x 30 mm, 3.0 mm i.d.) eluting with 0.0375% TFA in water (solvent A) and 0.01875% TFA in CH3CN (solvent B), using the following elution gradient 10-80% (solvent B) over 0.9 min and holding at 80% for 0.6 min at a flow rate of 1.2 mL/min.
Pharmaceutical Compositions
Example A
Tablets are prepared using conventional methods and are formulated as follows:
Ingredient Amount per tablet
Compound of Example I 5mg
Microcrystalline cellulose 100mg
Lactose 100mg
Sodium starch glycolate 30mg
Magnesium stearate 2mg
Total 237mg Example B
Capsules are prepared using conventional methods and are formulated as follows:
Ingredient Amount per tablet
Compound of Example 3 15mg
Dried starch 178mg
Magnesium stearate 2mg
Total 195mg
Biological Assay(s)
Materials: His-MBP-TEV-Full length human TNNI3K (hTNNI3K) was expressed in Baculokinase system and purified from amylase affinity column followed by Superdex200. The fluorescent ligand 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2- pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/- xanthen-9-yl)benzoic acid was used. The preparation of this fluorescent ligand is disclosed in U.S. Provisional Patent Application No. 61/237,815 filed August 28, 2009, the disclosure of which is incorporated by reference herein. The other buffer components, including MgCI2 (Catalog Number M1028), Bis-Tris (Catalog Number B7535), DTT (Catalog Number D9779) and Chaps (Catalog Number C3023) were purchased from Sigma-Aldrich.
Biological Assay Method I:
A fluorescent polarization assay was used to determine does response of compound inhibition on hTNNI3K ATP binding. The binding of 5-({[2-({[3-({4-[(5-hydroxy- 2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)- 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid to the hTNNI3K ATP binding pocket results in increase of fluorescent polarization and the displacement of 5-({[2-({[3-({4-[(5- hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino} carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid by a competitive compound leads to fluorescent polarization decrease.
Solution 1 : Ten (10) ml. of a 5 nM 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl) amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3- oxo-3H-xanthen-9-yl)benzoic acid solution (Solution 1 ) was prepared by mixing 5 μΙ_ of 1 M DTT and 80 μΙ_ of 10% (w/v) Chaps and 5 μΙ_ of a 10 μΜ 5-({[2-({[3-({4-[(5-hydroxy-2- methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino) ethyl]amino}carbonyl)- 2-(6-hydroxy-3-oxo-3/-/-xanthen-9-yl)benzoic acid stock solution into 9910 μΙ_ buffer (20 mM Tris, 15 mM MgCI2, pH 7.5). (Stock solution: 10 μΜ solution of 5-({[2-({[3-({4-[(5- hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)
ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/-xanthen-9-yl)benzoic acid in 100% DMSO).
Solution 2 was formed by mixing 53.8 μΙ_ of 2.6 μΜ hTNNI3K with a 6946.2 μΙ_ aliquot of Solution 1 (the above 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2- pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/- xanthen-9-yl)benzoic acid solution) to make up a 7 ml. of mixture of hTNNI3K and 5-({[2- ({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl} amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/-xanthen-9-yl)benzoic acid (Solution 2).
Fifty (50) nl_ of inhibitors in DMSO (or DMSO controls) were stamped into a 384-well low volume Greiner black plate, followed by addition of 5 μΙ_ of Solution 1 to column 18 and 5 μΙ_ Solution 2 to columns 1 -17 and 19-24 of the plate. The plate was then spun at 500 rpm for 30 seconds and incubated at rt for 60 min. After that, the fluorescent polarization was measured on Analyst (ex/em: 485/530 nm, Dichroic: 505). For dose response experiments, normalized data were fit by ABASE/XC50 and pXC50 = (log((b-y)/(y-a)))/d - log(x), where x is the compound concentration and y is the % activity at specified compound concentration, a is the minimum % activity, b is the maximum % activity, and d is the Hill slope.
The pXC50s are averaged to determine a mean value, for a minimum of 2 experiments. As determined using the above method, the compounds of Examples 1-55, 57-92, 94-205, 207-219, and 229-241 exhibited a pXC50 > 6.0. For instance, the compounds of Example 1 12 and Example 131 each inhibited hTNNI3K in the above method with a mean pXC50 of approximately 7.4.
Compounds of the present invention were tested for B-Raf protein kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays. A. B-Raf Enzyme Assay:
Compounds of the present invention were tested for B-Raf protein serine kinase inhibitory activity in a B-Raf Accelerated MEK ATPase assay (BRAMA). Baculovirus- expressed His6-tagged BRAFV600E full-length (amino acids 2-766) was used in the BRAMA assay. The BRAMA assay is a high sensitivity assay which measures an intrinsic MEK-mediated ATP hydrolysis uncoupled from downstream ERK phosphorylation by coupling the formation of ADP to NADH oxidation through the enzymes pyruvate kinase and lactate dehydrogenase. When ADP production is initiated by addition of catalytic amounts of an activated Raf enzyme and non-phosphorylated MEK, one observes robust ADP production concomitant with Raf-mediated phosphorylation of MEK. The method is disclosed in: C. Rominger, M. Schaber, E. May. Assay for B- Raf Activity Based on Intrinsic MEK ATPase Activity. Statutory Invention Registration 1 1/084,993 (March, 2005) but includes the following changes: 1 ) the assay was performed with a final MEK concentration of 150 nM and 2) the assay was read as single end point instead of a kinetic read.
Acceleration of MEK ATPase activity was determined from the data and plotted as a function of inhibitor concentration to afford concentration response curves, from which the plC50 values were generated following standard plC50 fitting protocol.
Many of the exemplified compounds Examples 1 -241 were run in the recited assay (A). The results are reported in the following Table 1 a in which the plC50 or average plC50, for one or more runs, of each assayed compound is categorized as indicated. In the following table:
plC50 values for the compounds of the examples were categorized by relative inhibition of B-Raf. The results are summarized in the tables below.
Table 1 a plC50 for B-Raf (BRAMA)
Figure imgf000229_0001
7, 14, 37, 39, 52, 54, 102, 104, 106,
1 13, 1 15, 1 16, 124, 137, 138, 150, 152,
6.0-7.5
153, 155, 156, 162, 167, 188, 189, 206,
207, 21 1 , 220, 240
B. Cellular assays - Cell Growth Inhibition Assay
Human colon tumor cells (Colo205) were cultured in RPMI (Mediatech 50-020-PB) containing 10% FBS and 1 % penicillin-streptomycin. Human melanoma cancer cells (SK- MEL-28) were cultured in EMEM with nonessential amino acids (Mediatech 50-01 1-PB) containing 10% FBS, 1 % sodium pyruvate (JT Baker 3354-04), and 1 % penicillin- streptomycin. All cell lines were maintained at 37 °C in a humidified 5% C02, 95% air incubator. Cells were harvested using trypsin/EDTA (Invitrogen 25200), counted using a haemocytometer, and plated. For 96-well assays (using white full-area NUNC plates cat. #136102), cells were plated in 105 μΙ_ at the following densities (cells/well): Colo205, 500; SK-MEL-28, 500. For 384-well assays (white full-area NUNC plates, cat. #781080), cells were plated in 48 μΙ_ at the following densities (cells/well): Colo205, 500; SK-MEL-28, 500.
The next day, compounds were diluted as follow: For 96-well assays, 13.5 μΙ_ of compound in DMSO were diluted using nine (9) serial 1 :3 dilutions of 4.5 μΙ_ in 9 μΙ_ of
DMSO. Medium (270 μί/ννβΙΙ of RPMI with 10% FBS and 1 % penicillin-streptomycin) was added to the plates. Aliquots (7 μΙ_) were added to cells in the final assay giving a final DMSO concentration of 0.2%. For 384-well assays, 15 μΙ_ of compound in DMSO were diluted using nine (9) serial 1 :3 dilutions of 5 μΙ_ in 10 μΙ_ of DMSO, followed by a further dilution of 5 μΙ_ of compound with 95 μΙ_ of medium, of which 2 μΙ_ were added to cells in the final assay giving a final DMSO concentration of 0.2%. Cells were incubated at 37 °C, 5% C02 for 3 days.
Total ATP was measured (as a surrogate estimate of cell number) using CellTiter- Glo® reagent (Promega G7571 ). Briefly, plates were removed from the incubator and allowed to equilibrate to room temperature for 30 min. CellTiter-Glo® (25 μΙ_ or 55 μΙ_ for 384-well or 96-well assays, respectively) reagent was added to each well and plates were shaken on an orbital plate shaker for 2 min. Plates were incubated without shaking for a further 30 min and read on an LJL Analyst GT reader in luminometer mode with an integration time of 0.5 seconds per well. Percent inhibition of cell growth was calculated relative to DMSO vehicle-treated control wells. Concentration of compound required to afford50% inhibition of vehicle-treated control cell growth (IC50) was interpolated using a 4- parameter fit for determining IC50 using the following equation: Y = A + ((B- A)/(1 +((C/X)AD))) where X = IC50.
Many of the compounds of Examples 1-228 were run in the recited assay and the results are reported in the following Table 2a in which the inhibition, or average inhibition for one or more runs of each assayed compound, is categorized as indicated. In the following table IC50 (nM) values for compounds of select examples were categorized by relative inhibition of cell proliferation.
Table 2a -Activity in Colo205 Tumor Cells
Figure imgf000231_0001
Many of the compounds of Examples 1-228 were run in the recited assay and the results are reported in the following Table 3a in which the inhibition, or average inhibition for one or more runs, of each assayed compound is categorized as indicated. In the following table IC50 (nM) values for compounds of select examples were categorized by relative inhibition of cell proliferation.
Table 3a - Activity in SK-MEL-28 Tumor Cells
Figure imgf000231_0002

Claims

What is claimed is:
1. A compound according to Formula I:
Figure imgf000232_0001
wherein:
R1 is (Ci-C4)alkyl;
X is N or CH;
Y is N or CR4;
Z is N or CR4;
R2 is H, halogen, (d-C8)alkyl, (C C8)haloalkyl, hydroxy(C C8)alkyl-,
(C1-C8)alkylthio-, (C C8)haloalkylthio-, (C3-C8)cycloalkylthio-, aryl, heteroaryl, -N(Ra)(Rb), or -ORc; wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, hydroxyl, (C1-C6)alkoxy, (Ci-C4)haloalkoxy, hydroxy(C C4)alkyl-, (C C4)alkoxy(Ci-C4)alkyl-, -N(Ra)(Rb), cyano, -CON(Ra)(Rb), -C02Rc, -CO(C C4)alkyl, -S02N(Ra)(Rb), -S02(C C4)alkyl,
-NHCO(Ci-C4)alkyl, or -NHS02(Ci-C4)alkyl;
each Ra is (Ci-C4)alkyl, which is optionally substituted one to three times, independently, by halogen, hydroxyl, (CrC6)alkoxy, amino, (Ci-C6)alkylamino,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino, -C02H, -C02(C C6)alkyl, -CONH2, -CONH(Ci-C6)alkyl, -CON((CrC6)alkyl)((Ci-C6)alkyl), or aryl, wherein said aryl is optionally substituted one to three times, independently, by halogen, hydroxyl, (Ci-C4)alkyl, (Ci-C4)haloalkyl,
(Ci-C4)alkoxy, (Ci-C4)haloalkoxy, hydroxy(Ci-C4)alkyl-, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -CONH2, -CONH(C C4)alkyl,
-CON((CrC4)alkyl)((Ci-C4)alkyl), -CO(C C4)alkyl, -C02(C C4)alkyl, -S02NH2,
-S02NH(CrC4)alkyl, -S02N((Ci-C4)alkyl)((C C4)alkyl), -S02(C C4)alkyl,
-NHCO(Ci-C4)alkyl, or -NHS02(Ci-C4)alkyl;
each Rb is H or (C C4)alkyl;
or Ra and Rb taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino,
(C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, hydroxyl, hydroxy(C1-C4)alkyl-, oxo, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkoxy(C1-C4)alkyl, or cyano;
R3 is H;
or R2 and R3 taken together with atoms through which they are connected form a non-aromatic 5-membered ring, which may be unsubstituted or substituted with one or two substituents independently selected from (d-C4)alkyl, (CrC4)haloalkyl,
hydroxy(CrC4)alkyl-, (CrC4)alkoxy, (Ci-C4)haloalkoxy, (CrC4)alkylthio-,
(Ci-C4)haloalkylthio-; -C02R , -(C C4)alkyl-C02R , -CORf , -CON(Rd)(Re), and
-(CrC4)alkyl-CON(Rd)(Re);
each R4 is independently selected from H, halogen, cyano, (Ci-C8)alkyl,
(C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C C4)haloalkyl, (C C4)alkoxy,
(Ci-C4)haloalkoxy, (C C4)alkylthio-, (C C4)haloalkylthio-, -C02R , -(C C4)alkyl-C02R , -CORf , -CON(Rd)(Re), -(Ci-C4)alkyl-CON(Rd)(Re), heterocycloalkyl, aryl, and heteroaryl; wherein the aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC4)alkyl, (C3-C6)cycloalkyl, (CrC4)haloalkyl, cyano, nitro, oxo,-ORc, -(Ci-C4)alkyl-ORc, -SRC, -(C C4)alkyl-SRc, -CO(Ci-C4)alkyl, -(d-d)alkyl- CO(C C4)alkyl, -CONHRd, -CON(Rd)(Re), -(C C4)alkyl-CON(Rd)(Re), -S02(C C4)alkyl, -(C1-C4)alkyl-S02(C1-C4)alkyl, -S02NHRd, -S02N(Rd)(Re), -(C C4)alkyl-S02N(Rd)(Re), -NHRd, -N(Rd)(Re), -(d-C4)alkyl-NHRd, -(C C4)alkyl-N(Rd)(Re), -C02Rf, -(C C4)alkyl- C02Rf, -NHS02(d-C4)alkyl, -(d-d)alkyl-NHS02(d-d)alkyl, -NHCO(d-d)alkyl, -(Ci-d)alkylNHCO(Ci-d)alkyl, -NHCOO(d-d)alkylphenyl,
-(Ci-d)alkylNHCOO(Ci-d)alkylphenyl, aryl, or heteroaryl;
wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (d-C6)alkyl, (C3-C6)cycloalkyl, (d-d)haloalkyl, cyano, nitro, -ORc, -N(Rd)(Re), -CON(Rd)(Re), -C02Rc, -CO(d-d)alkyl, -S02N(Rd)(Re),
-S02(Ci-d)alkyl,-NHCO(Ci-d)alkyl, or -NHS02(d-C4)alkyl,
Rc is H, (d-C6)alkyl, (d-d)cycloalkyl, or -(d-d)alkyl(C3-d)cycloalkyl, wherein said (d-C6)alkyl or (d-d)cycloalkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)haloalkyl, (d-d)alkoxy, amino,
(d-C4)alkylamino, ((Ci-d)alkyl)((C d)alkyl)amino, -C02H, -C02(d-d)alkyl, -CONH2, -CONH(Ci-d)alkyl, -CON((Ci-d)alkyl)((C d)alkyl), heterocycloalkyl, or aryl, wherein said aryl is optionally substituted one to three times, independently, by halogen, hydroxyl, (d-d)alkyl, (d-d)haloalkyl, (d-d)alkoxy, (d-d)haloalkoxy, hydroxy(d-C4)alkyl-, amino, (d-d)alkylamino, or ((d-C4)alkyl)((d-C4)alkyl)amino, -CONH2,
-CONH(d-d)alkyl, -CON((d-d)alkyl)((d-d)alkyl), -CO(d-d)alkyl, -C02(d-d)alkyl, -S02NH2, -S02NH(Ci-C4)alkyl, -S02N((C1-C4)alkyl)((C1-C4)alkyl), -S02(C C4)alkyl, -NHCO(d-C4)alkyl, or -NHS02(d-C4)alkyl;
Rd is independently selected from H, (C1-C4)alkyl, aryl, heterocycloalkyi or heterocycloalkyl-(Ci-C2)alkyl, wherein said (Ci-C )alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (CrC )alkoxy, amino, (Ci-C )alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, -C02H, -C02(C C4)alkyl, -CONH2, -CONH(Ci-C4)alkyl, or -CON((Ci-C )alkyl)((CrC )alkyl), and wherein any heterocycloalkyi is optionally substituted by (Ci-C )alkyl;
Re is (Ci-C4)alkyl;
or Rd and Re taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (Ci-C )alkyl, (Ci-C )haloalkyl, amino,
(Ci-C )alkylamino, ((Ci-C )alkyl)((Ci-C )alkyl)amino, hydroxyl, hydroxy(Ci-C )alkyl-, oxo, (Ci-C )alkoxy, (Ci-C )haloalkoxy, or (CrC )alkoxy(Ci-C )alkyl; and
R is H, (Ci-C )alkyl, cycloalkyl, 5-6-membered heterocycloalkyi, phenyl, or 5-6- membered heteroaryl, wherein said (Ci-C )alkyl, cycloalkyl, 5-6-membered
heterocycloalkyi, phenyl, or 5-6-membered heteroaryl is optionally substituted one to three times, independently, by (C1-C4)alkyl, hydroxyl, (d-d)alkoxy, amino, (C1-C4)alkylamino, ((d-d)alkyl)((d-d)alkyl)amino;
or a salt thereof.
2. The compound or salt according to claim 1 , wherein R1 is methyl or ethyl.
3. The compound or salt according to claim 1 or 2, wherein X is CH.
4. The compound or salt according to any one of claims 1 -3, wherein R2 is H, F, CI, Br, (d-d)alkyl, (d-C6)haloalkyl, hydroxy(d-C6)alkyl-, hydroxyl, (d-C6)alkoxy,
(d-C6)alkylthio-, (d-C6)haloalkoxy, (d-d)cycloalkoxy, (C3-C8)cycloalkyl(d-C6)alkoxy, (d-C6)alkylamino, ((d-C6)alkyl)((d-C6)alkyl)amino,
(hydroxy(d-C6)alkyl)((d-C6)alkyl)amino, ((d-d)alkoxy(d-d)alkyl)((d-d)alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl; wherein said pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one to two times, independently, by halogen, (d-C4)alkyl, (CrC4)haloalkyl, cyano, hydroxyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, hydroxy(CrC4)alkyl-, (Ci-C4)alkoxy(Ci-C4)alkyl-, amino, (Ci-C4)alkylamino, or
((Ci-C4)alkyl)((Ci-C4)alkyl)amino.
5. The compound or salt according to any one of claims 1 -3, wherein R2 and R3 taken together represent -CH2CH2-.
6. The compound or salt according to any one of claims 1 -5, wherein R4 is independently selected from H, F, CI, Br, (Ci-C6)alkyl, (CrC4)haloalkyl, (CrC4)alkoxy, (Ci-C4)haloalkoxy, (C C4)alkylthio-, cyano, -C02H, -C02(Ci-C4)alkyl, -CONH2,
-CONH(Ci-C4)alkyl- -CONH((C C4)alkyl)((Ci-C4)alkyl), -CO(pyrrolidin-l -yl), -
CO(piperidin-l -yl), -CO(piperazin-l-yl), -CO(morpholin-4-yl), -CO(thiomorpholin-4-yl), dihydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl;
wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one to two times, independently, by halogen, (CrC4)alkyl, (Ci-C4)haloalkyl, cyano, -C02H, -C02(CrC4)alkyl, -CONH2, -CONH(Ci-C4)alkyl, -CONH((Ci-C4)alkyl)((C C4)alkyl), -S02NH2,
-S02NH(CrC4)alkyl, -S02NH((Ci-C4)alkyl)((C C4)alkyl), carboxy(C C4)alkyl-,
phenyl(Ci-C2)alkyloxycarbonylamino(Ci-C4)alkyl-, hydroxyl, (CrC4)alkoxy,
(Ci-C4)haloalkoxy, hydroxy(CrC4)alkyl-, (CrC4)alkoxy(Ci-C4)alkyl-, amino,
(Ci-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, amino(Ci-C4)alkyl-,
(Ci-C4)alkylamino(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl- -NHCO(Ci-C4)alkyl, phenyl, halophenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl.
7. The compound or salt according to any one of claims 1 -6, wherein Y and Z are each independently CR4.
8. The compound or salt according to any one of claims 1-6, wherein Y is CR4 and Z is N.
9. The compound or salt according to any one of claims 1 -6, wherein Y is N and Z is CR4.
10. A compound which is:
3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-
(methyloxy)benzenesulfonamide,
3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide,
3-{[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/-methyl-4- (methyloxy)benzenesulfonamide,
3- {[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide,
4- (dimethylamino)-3-{[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
A/-methyl-4-(methyloxy)-3-{[5-(1-methyl-1 H-pyrazol-5-yl)-1 H-pyrrolo[2,3- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-(4-morpholinyl)-3-(1 /-/-pyrazolo[3,4-d]pyrimidin-4- ylamino)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methyloxy)benzenesulfonamide,
A/-methyl-4-(4-morpholinyl)-3-[(3-phenyl-1 /-/-pyrazolo[3,4-d]pyrimidin-4- yl)amino]benzenesulfonamide,
3-{[3-(3-chlorophenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
A/-methyl-3-[(3-methyl-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(4- morpholinyl)benzenesulfonamide,
3-{[3-(2-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide, 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[ethyl(2- hydroxyethyl)amino]-/\/-methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-{ethyl[2- (methyloxy)ethyl]amino}-/\/-methylbenzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4- (methyloxy)benzenesulfonamide,
3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4- (methyloxy)benzenesulfonamide,
/V-methyl-3-{[3-(5-methyl-2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4- (methyloxy)benzenesulfonamide,
3- [(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(1- methylethyl)oxy]benzenesulfonamide,
A/-methyl-4-(methyloxy)-3-{[3-(1-methyl-1 /-/-pyrazol-5-yl)-1 /-/-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
4-(dimethylamino)-3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
4- (dimethylamino)-/V-methyl-3-{[3-(5-methyl-2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin- 4-yl]amino}benzenesulfonamide,
4-(dimethylamino)-3-{[3-(2-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide ,
4-(dimethylamino)-/V-methyl-3-{[3-(1 -methyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
4-(dimethylamino)-/V-methyl-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-(methyloxy)-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-[(1 -methylethyl)oxy]-3-{[3-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-[(1 -methylethyl)oxy]-3-{[3-(1 -methyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
3-{[3-(2-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide,
A/-methyl-4-[(1 -methylethyl)oxy]-3-{[3-(5-methyl-2-furanyl)-1 H-pyrazolo[3,4- d]pyrimidin-4-yl]amino}benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-[(1 - methylethyl)oxy]benzenesulfonamide 3-{[3-(3,6-dihydro-2H-pyran-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methyl-4-[(1 -methylethyl)oxy]benzenesulfonamide,
/V-methyl-4-[(1 -methylethyl)oxy]-3-[(3-methyl-1 /-/-pyrazolo[3,4-d]pyrimidin-4- yl)amino]benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(cyclohexyloxy)-/\/- methylbenzenesulfonamide,
3- [(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(1 - pyrrolidinyl)benzenesulfonamide,
4- fluoro-/V-methyl-3-(9/-/-purin-6-ylamino)benzenesulfonamide,
A/-methyl-4-(4-morpholinyl)-3-(1 H-purin-6-ylamino)benzenesulfonamide,
/V-methyl-3-(1 /-/-purin-6-ylamino)-4-(1-pyrrolidinyl)benzenesulfonamide,
4-(dimethylamino)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-(methyloxy)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-(1 -piperidinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
A/-methyl-4-(4-methyl-1 -piperazinyl)-3-(1 H-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-[(1 -methylethyl)oxy]-3-(1 H-purin-6-ylamino)benzenesulfonamide, /V-methyl-4-(1-piperazinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
4-{ethyl[2-(methyloxy)ethyl]amino}-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[ethyl(2-hydroxyethyl)amino]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[(cyclohexylmethyl)oxy]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-(cyclopentyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
4-[(2-cyclohexylethyl)oxy]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-(cyclohexyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-3-(1 /-/-purin-6-ylamino)-4-{[2-(1 -pyrrolidinyl)ethyl]oxy}
benzenesulfonamide,
4-[3-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{[2-(1 -piperidinyl)ethyl]oxy}-3-(1 H-purin-6-ylamino)benzenesulfonamide
4-[4-(2-hydroxyethyl)-1 -piperidinyl]-/V-methyl-3-(1 H-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{[2-(4-piperidinyl)ethyl]oxy}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[ethyl(methyl)amino]-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-[4-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[2-(hydroxymethyl)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-3-(1 H-purin-6-ylamino)-4-[4-(trifluoromethyl)-1 - piperidinyl]benzenesulfonamide,
A/-methyl-3-(1 H-purin-6-ylamino)-4-[3-(trifluoromethyl)-1 - piperidinyl]benzenesulfonamide,
4-[3-(hydroxymethyl)-1 -pyrrolidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-[4-(dimethylamino)-1 -piperidinyl]-/V-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
4-(3-hydroxy-1 -pyrrolidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide,
4-(4-cyano-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, /V-methyl-4-{2-[2-(methyloxy)ethyl]-1-piperidinyl}-3-(1 H-purin-6- ylamino)benzenesulfonamide,
4-[2-(2-hydroxyethyl)-1 -piperidinyl]-/V-methyl-3-(1 H-purin-6- ylamino)benzenesulfonamide,
4-(3-hydroxy-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-(4-hydroxy-1 -piperidinyl)-/V-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide,
4-[2-(hydroxymethyl)-1 -pyrrolidinyl]-/V-methyl-3-(1 H-purin-6- ylamino)benzenesulfonamide,
4-(cycloheptyloxy)-/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-[(1 -methylpropyl)oxy]-3-(1 H-purin-6-ylamino)benzenesulfonamide, 4-[(1 ,2-dimethylpropyl)oxy]-/\/-methyl-3-(1 H-purin-6-ylamino)benzenesulfonamide,
/V-methyl-4-{[4-(methyloxy)cyclohexyl]oxy}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[(2,2,2- trifluoroethyl)oxy]benzenesulfonamide,
W-methyl-3-(1 H-purin-6-ylamino)-4-{[4-
(trifluoromethyl)cyclohexyl]oxy}benzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[(1 ,2-dimethylpropyl)oxy]-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4-methyl-1 - piperazinyl)benzenesulfonamide, 3-{[3-(3,6-dihydro-2H-pyran-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/- methyl-4-(methyloxy)benzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-/V-methyl-4-(1 - piperidinyl)benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-[3-(hydroxymethyl)-1 - piperidinyl]-/V-methyl benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-[4-(hydroxymethyl)-1 - piperidinyl]-/V-methyl benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-(4-hydroxy-1-piperidinyl)-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-(3-hydroxy-1-piperidinyl)-/\/- methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-/V-methyl-4-[(1- methylpropyl)oxy]benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-/V-methyl-4- (propyloxy)benzenesulfonamide,
3- [(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin -4-yl)amino]-4-(butyloxy)-/V- methylbenzenesulfonamide,
4- (4-fluoro-1-piperidinyl)-/\/-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide, A/-methyl-4-{3-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{2-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{4-[2-(methyloxy)ethyl]-1-piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-[3-(methyloxy)-1 -piperidinyl]-3-(1 H-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-[4-(methyloxy)-1 -piperidinyl]-3-(1 H-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-{4-[(methyloxy)methyl]-1 -piperidinyl}-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-4-(4-methyl-1 -piperidinyl)-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-3-(1 /-/-purin-6-ylamino)-4-[(2,2,2-trifluoroethyl)oxy] benzenesulfonamide,
4-(3,5-dimethyl-1-piperidinyl)-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
A/-methyl-3-(1 /-/-purin-6-ylamino)-4-[(3,3,3-trifluoropropyl)oxy]benzenesulfonamide, /V-methyl-3-(1 H-purin-6-ylamino)-4-[2-(trifluoromethyl)-1 -pyrrolidinyl]
benzenesulfonamide,
/V-methyl-3-(1 H-purin-6-ylamino)-4-[(3,3,3-trifluoro-1- methylpropyl)oxy]benzenesulfonamide,
4-(dimethylamino)-/\/-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide,
/V-ethyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide,
4-fluoro-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide, A/-methyl-4-(4-morpholinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-5-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-3-pyridinesulfonamide, 4-[ethyl(methyl)amino]-/\/-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(diethylamino)-/\/-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-[(2-hydroxyethyl)(methyl) amino]-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-[4-(2,2,2-trifluoroethyl)-1- piperazinyl]benzenesulfonamide,
/V-methyl-4-(methyloxy)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-[(1 -methylethyl)oxy]-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
W-methyl-4-(methylthio)-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-1 -(1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1 /-/-indole-6-sulfonamide, /V-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfonamide, 3-[(5-fluoro-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide, 3-[(5-chloro-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide, /V,4-dimethyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide, 3-[(5-chloro-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
3-[(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methyl benzenesulfonamide, 3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide, 3-[(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
3-[(5-chloro-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
1-(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)-/\/-methyl-2,3-dihydro-1 /-/-indole-6- sulfonamide,
3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4- (methylthio)benzenesulfonamide,
/V-methyl-3-({5-[4-(methyloxy)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl}amino)benzenesulfonamide,
/V-methyl-3-[(5-phenyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfonamide,
/V-methyl-3-{[5-(3-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[5-(4-chlorophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-methyl-3-{[5-(4-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[5-(2-chlorophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3-{[5-(3-chlorophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-methyl-3-{[5-(2-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-({5-[4-(dimethylamino)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3- ({5-[4-(aminomethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
/V-methyl-3-({5-[3-(trifluoromethyl)phenyl]-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl}amino)benzenesulfonamide,
/V-methyl-3-{[5-(4-pyridinyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
/V-methyl-3-{[5-(3-pyridinyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
4- [4-({3-[(methylamino) sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3-d]pyrimidin-5- yl]benzamide, 3-{[5-(3-aminophenyl)-1 H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3-{[5-(3-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3- {[5-(2-furanyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/\/-{4-[4-({3-[(methylamino)sulfonyl]phenyl} amino)-1 H-pyrrolo[2,3-d]pyrimidin-5- yl]phenyl}acetamide,
4- [4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 H-pyrrolo[2,3-d]pyrimidin-5- yl]benzoic acid,
3-({5-[3-(aminomethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3-{[5-(4-fluorophenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
{4-[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 H-pyrrolo[2,3-d]pyrimidin-5- yl]phenyl}acetic acid,
3-({5-[4-(aminosulfonyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
phenylmethyl (2-{4-[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3- d]pyrimidin-5-yl]phenyl}ethyl)carbamate,
3-{[5-(4'-chloro-4-biphenylyl)-1 H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3- [(5-cyano-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide, A/-methyl-3-{[5-(1 -methylethyl)-1 H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
A/-methyl-4-(1 -pyrrolidinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-4-(1 -piperidinyl)-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-(2-methyl-1 -pyrrolidinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4- (2,5-dimethyl-1-pyrrolidinyl)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(3,5-dimethyl-1-piperidinyl)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide, /V-methyl-4-(4-methyl-1 -piperidinyl)-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-(3-methyl-1 -piperidinyl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-4-[(2R)-2-methyl-1 -pyrrolidinyl]-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-(4- thiomorpholinyl)benzenesulfonamide,
/V-methyl-4-[(2S)-2-methyl-1-pyrrolidinyl]-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(4,4-dimethyl-1-piperidinyl)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-[(3R,5S)-3,5-dimethyl-1-piperidinyl]-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
3-[(6-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methylbenzenesulfonamide,
3- [(5,6-dibromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/- methylbenzenesulfonamide,
4- ({3-[(methylamino) sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3-d]pyrimidine-6- carboxylic acid,
1 , 1 -dimethylethyl 4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 /-/-pyrrolo[2,3- d]pyrimidine-6-carboxylate,
1-methylethyl 4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 H-pyrrolo[2,3- d]pyrimidine-6-carboxylate,
3-[(6-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-/\/- methylbenzenesulfonamide,
3-[(6-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4- morpholinyl)benzenesulfonamide,
/V-methyl-3-{[6-(1 -pyrrolidinylcarbonyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
/V-methyl-3-[(6-phenyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfonamide, /V-methyl-3-{[6-(2-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[6-(2-hydroxyphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-methyl-3-({6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4- yl}amino)benzenesulfonamide, 3-({6-[3-(hydroxymethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3-({6-[4-(1 -dimethylethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
3-{[6-(4-hydroxyphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-methyl-3-{[6-(4-pyridinyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
/V-methyl-3-{[6-(4-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
/V-methyl-3-{[6-(3-methylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[6-(3,5-dimethylphenyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
3-{[6-(3-chloro-4-pyridinyl)-1 H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-/\/- methylbenzenesulfonamide,
/V-methyl-3-({6-[5-(1 -methylethyl)-2-(methyloxy)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin- 4-yl}amino)benzenesulfonamide,
3- ({6-[4-(hydroxymethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-/\/- methylbenzenesulfonamide,
1 , 1 -dimethylethyl 3-[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrrolo[2,3- d]pyrimidin-6-yl]benzoate,
/V-methyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-4-dimethyl-3-(1 /-/-purin-6-ylamino)benzenesulfonamide,
/V-methyl-3-(1 H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzenesulfonamide,
4- (dimethylamino)-/V-methyl-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
A/-methyl-1 -(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1 H-indole-6- sulfonamide,
4-(dimethylamino)-/\/-methyl-3-({6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3- d]pyrimidin-4-yl}amino)benzenesulfonamide,
/V-methyl-4-(4-morpholinyl)-3-({6-[3-(trifluoromethyl)phenyl]-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl}amino)benzenesulfonamide,
/V-methyl-4-(methyloxy)-3-({6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin- 4-yl}amino)benzenesulfonamide, /V-methyl-1-{6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3-d]pyrimidin-4-yl}-2,3- dihydro-1 /-/-indole-6-sulfonamide,
/V-methyl-4-(methyloxy)-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
/V-methyl-4-(methyloxy)-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
/V-methyl-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(4- morpholinyl)benzenesulfonamide,
/V-methyl-4-(methylthio)-3-({6-[3-(trifluoromethyl)phenyl]-1 H-pyrrolo[2,3- d]pyrimidin-4-yl}amino)benzenesulfonamide,
4-(dimethylamino)-/\/-methyl-3-{[6-(1 -pyrrolidinylcarbonyl)-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl]amino}benzenesulfonamide,
A/-methyl-4-(4-morpholinyl)-3-{[6-(1-pyrrolidinylcarbonyl)-1 /-/-pyrrolo[2,3- d]pyrimidin-4-yl]amino}benzenesulfonamide,
W-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-[(2,2,2- trifluoroethyl)oxy]benzenesulfonamide,
4-(ethyloxy)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-hydroxy-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide, A/-methyl-4-(propylamino)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methyl-2-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-biphenylsulfonamide,
/V-methyl-2-({6-[3-(trifluoromethyl)phenylH
biphenylsulfonamide,
A/-methyl-4-(1 -methyl-1 H-pyrazol-5-yl)-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
A/-methyl-4-(1 -methyl-1 H-pyrazol-5-yl)-3-({6-[3-(trifluoromethyl)phenyl]-1 H- pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzenesulfonamide,
/V-methyl-3-{[5-(2-methylpropyl)-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl]amino}benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/V-methyl-4-(4-methyl-1- piperidinyl)benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/\/-methyl-4-{4- [(methyloxy)methyl]-1-piperidinyl}benzenesulfonamide,
3-{[3-(3-furanyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(4-hydroxy-1 - piperidinyl)-/V-methylbenzenesulfonamide, 3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(3-hydroxy-1 - piperidinyl)-/V-methylbenzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[4- (trifluoromethyl)-1-piperidinyl]benzenesulfonamide,
3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-{4- [(methyloxy)methyl]-1-piperidinyl}benzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-[4-(methyloxy)-1 - piperidinyl]benzenesulfonamide,
3- [(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(4-methyl-1 - piperidinyl)benzenesulfonamide,
/V-methyl-4-({[3-(methyloxy)phenyl]methyl}amino)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
/V-methyl-4-({[3-(methyloxy)phenyl]methyl}oxy)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
/V-methyl-4-(methyl{[3-(methyloxy)phenyl]methyl}amino)-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
/V-methyl-4-(2-methyl-1 -pyrrolidinyl)-3-(1 H-purin-6-ylamino)benzenesulfonamide
4- [[(3-hydroxyphenyl)methyl](methyl)amino]-/\/-methyl-3-(1 /-/-purin-6- ylamino)benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-4-(3-hydroxy-1 - piperidinyl)-/V-methylbenzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-/\/-methyl-4-(2-methyl-1 - pyrrolidinyl)benzenesulfonamide,
3-{[3-(3-furanyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-/V-methyl-4-(2-methyl-1- pyrrolidinyl)benzenesulfonamide,
3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[ethyl(methyl)amino]-/\/- methylbenzenesulfonamide,
/V-methyl-4-[(2S)-2-methyl-1-pyrrolidinyl]-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
4-(4,4-difluoro-1 -piperidinyl)-/V-methyl-3-(1 /-/-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
/V-methy-3-{1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-[(2R)-2-trifluoromethyl)- pyrrolidinyl]benzenesulfonamide,
/V-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-[(2R)-2- (trifluoromethyl)-1-pyrrolidinyl]benzenesulfonamide, 3- [(5-bromo-1 H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/V-methyl-4-[(2S)-2-m pyrrolidinyl]benzenesulfonamide,
/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4- [(trifluoromethyl)oxy]benzenesulfonamide,
4-fluoro-/V-methyl-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
4- (2,5-dimethyl-1-pyrrolidinyl)-/V-methyl-3-[(5-methyl-1 H-pyrrolo[2,3-d]pyrimi yl)amino]benzenesulfonamide,
4-chloro-/V-methyl-3-[(5-methyl-1 /-/-pyrrolo[2,3-d]pyrimidin-4- yl)amino]benzenesulfonamide,
4-chloro-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4-ylam
/V-methyl-4-[methyl(2,2,2-trifluoroethyl)amino]-3-(1 H-pyrrolo[2,3-d]pyrimi ylamino)benzenesulfonamide,
4-(3,3-difluoro-1 -pyrrolidinyl)-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide,
4-(3,3-difluoro-1 -piperidinyl)-/V-methyl-3-(1 H-pyrrolo[2,3-d]pyrimidin-4- ylamino)benzenesulfonamide, or
or a salt thereof.
1 1 . A pharmaceutical composition comprising the compound or salt according to any one of claims 1 -10 and one or more pharmaceutically-acceptable excipients.
12. A method for treating congestive heart failure comprising administering to a patient in need thereof an effective amount of the compound or salt according to any one of claims 1-10.
13. A method for treating congestive heart failure comprising administering to a patient in need thereof the pharmaceutical composition according to claim 1 1.
14. A method for treating a susceptible neoplasm comprising administering to a patient in need thereof an effective amount of the compound or salt according to any one of claims 1-10.
15. A method for treating a susceptible neoplasm comprising administering to a patient in need thereof the pharmaceutical composition according to claim 1 1.
16. The method according to claim 14 or 15, wherein the susceptible neoplasm is selected from the group consisting of Barret's adenocarcinoma, billiary tract carcinomas, breast cancer, cervical cancer, cholangiocarcinoma, glioblastomas, astrocytomas, ependymomas, large intestinal colon carcinoma, gastric cancer, squamous cell carcinoma of the head and neck, acute lymphoblastic leukemia, acute myelogenous leukemia, myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non- Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma, erythroleukemia, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer, sarcoma, melanomas, and thyroid cancers.
PCT/US2011/037533 2010-05-24 2011-05-23 Compounds and methods WO2011149827A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34761310P 2010-05-24 2010-05-24
US61/347,613 2010-05-24

Publications (1)

Publication Number Publication Date
WO2011149827A1 true WO2011149827A1 (en) 2011-12-01

Family

ID=45004306

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/037533 WO2011149827A1 (en) 2010-05-24 2011-05-23 Compounds and methods

Country Status (1)

Country Link
WO (1) WO2011149827A1 (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026516A1 (en) * 2011-08-23 2013-02-28 Merck Patent Gmbh Bicyclic heteroaromatic compounds
WO2014044691A1 (en) * 2012-09-20 2014-03-27 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyrimidinylamino-benzothiazolones as mknk kinase inhibitors
CN104119342A (en) * 2013-04-25 2014-10-29 苏州科捷生物医药有限公司 Method for preparing high purity 4-chloro-5-methyl-7H-pyrrole [2,3-d] pyrimidine
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
US9296757B2 (en) 2012-05-21 2016-03-29 Bayer Pharma Aktiengesellschaft Substituted benzothienopyrimidines
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
CN109422748A (en) * 2017-08-21 2019-03-05 南京理工大学 The method for synthesizing TNNI3K inhibitor
CN109734674A (en) * 2019-02-26 2019-05-10 中国药科大学 Phenyl amines WDR5 protein-protein interaction inhibitor and its preparation method and purposes
CN109952306A (en) * 2016-04-19 2019-06-28 加利福尼亚大学董事会 ErbB inhibitor and application thereof
JP2019535673A (en) * 2016-10-21 2019-12-12 ニンバス ラクシュミ， インコーポレイテッド TYK2 inhibitors and uses thereof
CN112794855A (en) * 2019-11-13 2021-05-14 中国药科大学 N-aryl pyrimidine-4-amine derivative and application thereof
US11020398B2 (en) 2016-08-24 2021-06-01 Arqule, Inc. Amino-pyrrolopyrimidinone compounds and methods of use thereof
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
CN114957262A (en) * 2022-06-02 2022-08-30 浙江工业大学 Preparation method of C-6-arylation deazapurine derivative
US11479545B2 (en) 2018-04-23 2022-10-25 China Pharmaceutical University Compositions and methods for inhibiting phenyl triazole MLL1-WDR5 protein-protein interaction

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070259904A1 (en) * 2005-11-01 2007-11-08 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
EP1382339B1 (en) * 1999-12-10 2007-12-05 Pfizer Products Inc. Compositions containing pyrrolo ¬2,3-d pyrimidine derivatives
US7593820B2 (en) * 2005-05-12 2009-09-22 Cytopia Research Pty Ltd Crystal structure of human Janus Kinase 2 (JAK2) and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1382339B1 (en) * 1999-12-10 2007-12-05 Pfizer Products Inc. Compositions containing pyrrolo ¬2,3-d pyrimidine derivatives
US7593820B2 (en) * 2005-05-12 2009-09-22 Cytopia Research Pty Ltd Crystal structure of human Janus Kinase 2 (JAK2) and uses thereof
US20070259904A1 (en) * 2005-11-01 2007-11-08 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9249140B2 (en) 2011-08-23 2016-02-02 Merck Patent Gmbh Bicyclic heteroaromatic compounds
AU2012299899B2 (en) * 2011-08-23 2016-09-15 Merck Patent Gmbh Bicyclic heteroaromatic compounds
WO2013026516A1 (en) * 2011-08-23 2013-02-28 Merck Patent Gmbh Bicyclic heteroaromatic compounds
US9296757B2 (en) 2012-05-21 2016-03-29 Bayer Pharma Aktiengesellschaft Substituted benzothienopyrimidines
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
US9642855B2 (en) 2012-06-29 2017-05-09 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
WO2014044691A1 (en) * 2012-09-20 2014-03-27 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyrimidinylamino-benzothiazolones as mknk kinase inhibitors
JP2015529232A (en) * 2012-09-20 2015-10-05 バイエル・ファルマ・アクティエンゲゼルシャフト Substituted pyrrolopyrimidinylamino-benzothiazolone
US9382255B2 (en) 2012-09-20 2016-07-05 Bayer Pharma Aktiengesellschaft Substituted pyrrolopyrimidinylamino-benzothiazolones as MKNK kinase inhibitors
CN104119342A (en) * 2013-04-25 2014-10-29 苏州科捷生物医药有限公司 Method for preparing high purity 4-chloro-5-methyl-7H-pyrrole [2,3-d] pyrimidine
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US11020400B2 (en) 2015-12-23 2021-06-01 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US10933065B2 (en) 2015-12-23 2021-03-02 Arqule Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US10245263B2 (en) 2015-12-23 2019-04-02 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
CN109952306A (en) * 2016-04-19 2019-06-28 加利福尼亚大学董事会 ErbB inhibitor and application thereof
EP3445768A4 (en) * 2016-04-19 2019-12-18 The Regents of The University of California Erbb inhibitors and uses thereof
US11020398B2 (en) 2016-08-24 2021-06-01 Arqule, Inc. Amino-pyrrolopyrimidinone compounds and methods of use thereof
JP2019535673A (en) * 2016-10-21 2019-12-12 ニンバス ラクシュミ， インコーポレイテッド TYK2 inhibitors and uses thereof
JP7082120B2 (en) 2016-10-21 2022-06-07 ニンバス ラクシュミ， インコーポレイテッド TYK2 inhibitors and their use
US11396508B2 (en) 2016-10-21 2022-07-26 Nimbus Lakshmi, Inc. TYK2 inhibitors and uses thereof
CN109422748A (en) * 2017-08-21 2019-03-05 南京理工大学 The method for synthesizing TNNI3K inhibitor
US11479545B2 (en) 2018-04-23 2022-10-25 China Pharmaceutical University Compositions and methods for inhibiting phenyl triazole MLL1-WDR5 protein-protein interaction
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
CN109734674A (en) * 2019-02-26 2019-05-10 中国药科大学 Phenyl amines WDR5 protein-protein interaction inhibitor and its preparation method and purposes
CN109734674B (en) * 2019-02-26 2022-08-26 中国药科大学 Aniline WDR5 protein-protein interaction inhibitor and preparation method and application thereof
CN112794855A (en) * 2019-11-13 2021-05-14 中国药科大学 N-aryl pyrimidine-4-amine derivative and application thereof
CN112794855B (en) * 2019-11-13 2023-07-28 中国药科大学 Preparation method and application of N-aryl pyrimidine-4-amine derivative
CN114957262A (en) * 2022-06-02 2022-08-30 浙江工业大学 Preparation method of C-6-arylation deazapurine derivative
CN114957262B (en) * 2022-06-02 2023-11-17 浙江工业大学 Preparation method of C-6-position arylation deazapurine derivative

Similar Documents

Publication Publication Date Title
WO2011149827A1 (en) Compounds and methods
JP6749444B2 (en) 4-Imidazopyridazin-1-yl-benzamide and 4-imidazotriazin-1-yl-benzamide as BTK inhibitors
US20200392132A1 (en) Tetrahydro-Pyrido-Pyrimidine Derivatives
JP7041070B2 (en) Amine-substituted aryl or heteroaryl compounds as EHMT1 and EHMT2 inhibitors
CA2976741C (en) 1-cyano-pyrrolidine compounds as usp30 inhibitors
AU2014324595B2 (en) Substituted nicotinimide inhibitors of BTK and their preparation and use in the treatment of cancer, inflammation and autoimmune disease
JP2022106953A (en) Piperidine derivatives as inhibitors of ubiquitin specific protease 7
JP2018150358A (en) Tank-binding kinase inhibitor compounds
WO2018206539A1 (en) Heteroaryl compounds that inhibit g12c mutant ras proteins
ES2654288T3 (en) P2X7 modulators
EP3102579A2 (en) Heterocyclic compounds
AU2018389145A1 (en) Exo-aza spiro inhibitors of menin-MLL interaction
JP2024506909A (en) HPK1 antagonists and their uses
WO2022007921A1 (en) Triazine compound and composition and use thereof
WO2011056739A1 (en) Compounds and methods
CN113683629B (en) Substituted heteroaryl compounds, compositions and uses thereof
AU2014253493B2 (en) Tetrahydro-pyrido-pyrimidine derivatives
ES2822586T3 (en) Substituted nicotinimide-type btk inhibitors and their preparation and use in the treatment of cancer, inflammation, and autoimmune diseases
KR20230164602A (en) Heterocyclic compound as diacrylglycerol kinases inhibitor and use thereof
TW202225163A (en) Aromatic heterocyclic compound, and pharmaceutical composition and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11787185

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11787185

Country of ref document: EP

Kind code of ref document: A1